Chondrodysplasia with disorder of sex development syndrome is a very rare genetic condition that affects both the bones and the way the sex organs and sex chromosomes work together. In most reported patients, the chromosomes are 46,XY (usually linked with male development), but the gonads (testes) do not form normally, and the baby is often born with a female-looking body or unclear genital appearance. Children usually have very short height and many changes in the shape of their bones.
Chondrodysplasia with disorder of sex development syndrome is an ultra-rare genetic condition. It affects the growth of bones (a skeletal dysplasia) and the way the baby’s sex organs and gonads develop (a disorder of sex development, DSD). Children may have short stature, bent or shortened limbs, joint problems, and differences in external genitalia or internal gonads. [1]
Researchers link this syndrome to changes in the HHAT gene, which is important for “Hedgehog” signalling, a pathway that controls early cartilage, bone, and gonadal development. [2] Because the gene is affected from early pregnancy, the condition is present at birth. There is no simple cure. Treatment focuses on symptoms, protecting organs, helping growth, supporting puberty, and looking after the child’s and family’s emotional health. [3]
Doctors place this condition in two big groups at the same time: “skeletal dysplasias” (diseases that change bone growth) and “disorders of sex development (DSD)” (conditions where the development of gonads, hormones, or genital organs is different from the usual pattern). It is inherited in an autosomal recessive way, which means a child usually needs to get a changed copy of the gene from both parents.
Researchers have shown that many people with this syndrome have disease-causing changes in a gene called HHAT (hedgehog acyltransferase). This gene helps control the “hedgehog” signaling pathway, which is very important for early growth of cartilage, bones, brain, and gonads. When HHAT does not work well, bone growth is severely disturbed, and testis development in a 46,XY fetus can fail, leading to complete gonadal dysgenesis and a DSD picture.
Because this disease is extremely rare, most of what we know comes from a small number of families and case reports. Reports describe severe short stature, small head (microcephaly), seizures, cerebellar vermis hypoplasia, and complete 46,XY gonadal dysgenesis in the same person, which together make this syndrome very distinct.
Other names
Over time, different doctors and databases have used several names for this syndrome. All of the names below refer to the same basic condition, even if the wording is slightly different.
Common other names include:
Nivelon-Nivelon-Mabille syndrome
Chondrodysplasia-pseudohermaphroditism syndrome (older term)
Chondrodysplasia-disorder of sex development syndrome
Chondrodysplasia with disorder of sex development syndrome
Chondrodysplasia-difference of sex development syndrome
Pseudohermaphroditism and chondrodysplasia
NNMS (short form for Nivelon-Nivelon-Mabille syndrome)
The older word “pseudohermaphroditism” is now avoided in modern medicine because it is confusing and can feel disrespectful. Today, experts prefer the term “disorder” or “difference of sex development (DSD)” for these conditions.
There is no official medical subtype classification of this syndrome yet, because so few patients have been reported. However, for simple understanding, doctors sometimes think of “practical types” based on the most visible problems:
Type 1 – Classic form: very severe short stature, clear generalized chondrodysplasia, and complete 46,XY gonadal dysgenesis with female-appearing external genitalia.
Type 2 – Neurologic-plus form: classic skeletal and DSD features plus very strong brain involvement, such as marked microcephaly, cerebellar vermis hypoplasia, and early-onset seizures.
Type 3 – Milder or “incomplete” form (theoretical grouping): skeletal and DSD features are present but slightly less severe, or some features such as seizures or eye problems are missing, which can make diagnosis more difficult.
These “types” are only teaching labels to help describe how different children with the same gene problem may look, not official separate diseases.
Causes
A single basic cause lies behind this syndrome: a disease-causing change in a gene important for bone and gonadal development, most often the HHAT gene, passed in an autosomal recessive pattern. The 20 points below describe the key genetic and biological mechanisms that cause or explain the features of the syndrome.
1. Autosomal recessive inheritance – The disease usually appears when a child receives one abnormal copy of the same gene from each parent. The parents are often healthy “carriers” with one normal and one changed copy, so the condition may appear suddenly in a family.
2. Pathogenic variants in the HHAT gene – Many reported patients have mutations in HHAT, which encodes an enzyme that modifies hedgehog proteins. Faulty HHAT leads to poor hedgehog signaling and abnormal bone and gonadal development, creating the core picture of the syndrome.
3. Disrupted hedgehog signaling pathway – Hedgehog proteins guide early patterning of the skeleton, face, brain, and gonads. When HHAT cannot modify these proteins correctly, the signal is weak, and many organs, especially cartilage and bone, do not grow in their normal shape and size.
4. Abnormal growth plates in long bones – In skeletal dysplasias, the cartilage at the ends of long bones (growth plates) does not turn into bone in the usual way. This leads to short limbs (micromelia), brachydactyly, and severe short stature that are typical in this syndrome.
5. Generalized chondrodysplasia – “Chondrodysplasia” means abnormal cartilage development throughout the skeleton. In this syndrome, growth plates in many bones are involved, giving a bell-shaped chest, pelvic changes, and broad long bones on imaging.
6. 46,XY complete gonadal dysgenesis – Genetic studies show that affected people often have 46,XY chromosomes, but the testes fail to form or function. Without normal testes, typical male hormones (like testosterone) and anti-Müllerian hormone are missing, so external genitalia may look female even though chromosomes are XY.
7. Primary gonadal failure and hormone lack – Because the gonads are streak-like or absent, they cannot produce enough sex steroids during fetal life or puberty. This hormone lack causes incomplete sex differentiation before birth and absent puberty in adolescence.
8. Disrupted brain and cerebellar development – Many patients have cerebellar vermis hypoplasia and microcephaly. The same HHAT-hedgehog pathway involved in bone development also guides early brain patterning, so gene changes can lead to structural brain differences and later seizures.
9. Intrauterine growth restriction (IUGR) – Fetuses with this syndrome often grow poorly inside the womb and are “small for gestational age” at birth. This is likely due to the global effect of the gene defect on skeletal, muscular, and sometimes placental development.
10. Severe postnatal growth failure – After birth, the same bone and cartilage problems continue to limit growth, so height remains far below average, and the child often has severe proportional dwarfism.
11. Consanguinity (parents related by blood) – Because this disease follows an autosomal recessive pattern and is extremely rare, reported families often have parents who are related (such as cousins), which increases the chance that both carry the same gene change.
12. Modifier genes in skeletal development – Reviews of skeletal dysplasias show that several genes interact in bone growth. Other variants besides HHAT may slightly change the severity of limb shortening or spine deformity, which explains why some children are more severely affected than others.
13. Modifier genes in sex development – DSD reviews describe many genes (such as SRY, SOX9, NR5A1 and others) that act together to form testes in a 46,XY fetus. Changes in these or related regulatory genes may worsen the gonadal dysgenesis in some individuals who already have the HHAT defect.
14. Hypergonadotropic hypogonadism – When gonads do not work, the brain releases more LH and FSH to try to stimulate them. Over time, this high LH/FSH with low sex steroids becomes a stable pattern (hypergonadotropic hypogonadism) and is a direct hormonal “cause” of many puberty and fertility problems seen in the syndrome.
15. Eye and cranial bone development defects – The same early developmental pathways that shape the skeleton also shape the skull and eyes. This explains why some patients have iris hypoplasia, coloboma, deep-set eyes, and increased skull bone thickness together with their bone and DSD features.
16. Muscular hypoplasia and weakness – Poor growth of bones and nerves can lead to thin muscles and low muscle bulk. This makes movement slower and may delay motor milestones in infancy and childhood.
17. Seizure tendency from structural brain changes – Cerebellar and cerebral hypoplasia can disturb electrical activity in the brain. This structural problem is one of the reasons why seizures are frequent in some reported patients.
18. Global developmental brain effect – The same gene defects that change skull and cerebellar growth may also affect cortical development and brain connectivity. This broad effect on the brain helps explain mild to moderate intellectual disability and learning difficulties in many individuals.
19. Very low disease frequency (ultra-rare genetics) – Because the disease is so rare (estimated well below 1 in 1,000,000), random genetic drift and “founder effects” in small populations can play a role. This means the same rare variant can appear in more than one child within a small community.
20. Non-genetic factors as modifiers, not primary cause – Environmental or pregnancy factors (like poor nutrition or other illnesses) do not cause this syndrome by themselves, but they can worsen growth, bone health, or seizure control in a child who already has the gene defect. Good supportive care can reduce the impact of these extra stresses.
Symptoms
Symptoms can be very severe and usually appear before birth or in the newborn period. Not every person has all the features listed, but they help doctors think about this syndrome.
1. Severe short stature (dwarfism) – Children with this syndrome are much shorter than other children of the same age, even compared with other family members. The shortness is usually proportionate, meaning the whole body is small, not only the limbs.
2. Limb shortening (micromelia and brachydactyly) – The arms, legs, hands, and feet are often shorter than usual. Fingers and toes can be stubby and broad. This comes from the underlying chondrodysplasia affecting the growth plates of long bones.
3. Abnormal chest shape (narrow or bell-shaped thorax) – The rib cage may be narrow with a bell-shaped appearance. This can sometimes affect breathing and may be seen clearly on chest X-rays.
4. Pelvic and shoulder bone changes – Imaging often shows abnormal pelvic girdle and shoulder bones. These changes help radiologists and geneticists recognize the pattern of this particular skeletal dysplasia.
5. Facial differences (dysmorphic features) – Many children have deep-set eyes, upslanting eye openings, puffy eyelids, large ears and mouth, and mild forward projection of the lower jaw. These features are not harmful by themselves but are useful clues for diagnosis.
6. Eye problems – Eye findings can include underdeveloped irises (iris hypoplasia), coloboma (a “hole” in part of the eye tissue), myopia, and other structural changes. These issues may affect vision and often require regular care by an eye specialist.
7. Small head and brain differences (microcephaly and cerebellar vermis hypoplasia) – The head size is often clearly smaller than average, and brain imaging can show underdevelopment of the cerebellar vermis and sometimes other brain regions. These differences increase the risk of seizures and developmental delay.
8. Seizures – Some infants develop seizures early in life. Seizures may vary in type and can be difficult to control in some cases, so children often need a pediatric neurologist and antiepileptic medicines.
9. Muscle weakness and low muscle bulk – Muscles can be thin and underdeveloped (muscular hypoplasia). Babies may feel “floppy” at first and take longer to sit, stand, and walk because of weak muscle power and abnormal bones.
10. Intellectual disability or learning difficulties – Some children have mild to moderate intellectual disability. They may walk and talk later than usual and need special support in school. The degree of learning difficulty can vary between individuals.
11. Atypical or ambiguous genital appearance in 46,XY individuals – At birth, the external genitalia can look typically female, slightly ambiguous, or different from the usual male or female pattern. This occurs because the gonads have not produced enough hormones to drive male genital development.
12. Lack of puberty (delayed or absent sexual development) – As the child grows into a teenager, breasts, menstrual periods, testicular enlargement, or other puberty signs may not appear because the gonads cannot make sex hormones. Doctors often discover the condition when they investigate delayed puberty.
13. Primary amenorrhea in people raised as girls – Individuals who are raised as girls, but have 46,XY chromosomes and gonadal dysgenesis, often never start menstruating. This “no first period” (primary amenorrhea) is a key sign that leads to DSD and chromosomal testing.
14. Hormonal pattern of hypergonadotropic hypogonadism – Blood tests usually show very high LH and FSH with low estrogen or testosterone, meaning the brain is trying to stimulate gonads that cannot respond. This hormonal pattern explains many puberty and fertility problems.
15. Before-birth and after-birth growth retardation – Many affected fetuses are small on prenatal ultrasound and remain small after birth, with poor weight gain and length despite adequate nutrition. This global growth failure is part of the syndrome rather than only a feeding problem.
Diagnostic tests
Because this syndrome is so rare and complex, diagnosis needs a careful, step-by-step approach that combines clinical examination, genetic testing, hormone tests, and imaging. A multidisciplinary team (pediatrics, endocrinology, genetics, neurology, radiology, psychology, and surgery) usually works together.
Physical exam tests
1. Full newborn and child physical examination – The doctor carefully examines the whole body, including head size, face, chest, abdomen, spine, arms, and legs. They look for very short stature, limb shortening, abnormal chest shape, and other visible differences. This first step guides which specialized tests are needed next.
2. Growth and body proportion assessment – Height, weight, and head circumference are plotted on growth charts. Sitting height, leg length, and arm span can show if short stature is proportionate or mainly in the limbs. The pattern of growth failure helps distinguish this syndrome from other causes of short stature.
3. Musculoskeletal and spine examination – The doctor inspects and palpates the ribs, pelvis, spine, and joints, looking for a narrow thorax, abnormal pelvic shape, broad long bones, or spine curvature. These findings point toward a generalized chondrodysplasia rather than an isolated bone problem.
4. Neurologic and developmental evaluation – Muscle tone, strength, reflexes, coordination, and developmental milestones are checked. Microcephaly, delayed motor skills, and signs of cerebellar involvement (such as poor balance) suggest a syndromic diagnosis rather than a simple skeletal disorder alone.
Manual (bedside) tests
5. Detailed external genital examination with DSD scoring – The clinician gently inspects the genital region and may use scoring systems such as Prader or other DSD scales to describe the appearance. This helps document whether the genitalia look typically female, male, or ambiguous in a 46,XY person.
6. Palpation for gonads in groin and abdomen – The doctor carefully feels in the inguinal region and abdomen to see if any gonadal tissue (testes) can be felt. In this syndrome, gonads are often absent or streak-like, and may not be palpable at all.
7. Anthropometric body measurements – Using a measuring tape and calipers, the clinician measures limb lengths, hand and foot sizes, and segment ratios. The pattern of micromelia and brachydactyly supports the diagnosis of a generalized skeletal dysplasia such as this one.
8. Bedside vision and hearing checks – Simple tools like a light, toys, or sound-making devices can be used to screen for eye and hearing problems. Abnormal responses may reflect eye anomalies or neurological involvement, which are part of the described clinical spectrum.
Laboratory and pathological tests
9. Karyotype (chromosome analysis) – A blood sample is taken to look at the chromosomes. In this syndrome, the common result is 46,XY in a person who may have female-appearing or ambiguous genitalia. Finding 46,XY with the clinical picture strongly supports the diagnosis of a DSD.
10. Hormone profile (LH, FSH, sex steroids, AMH, 17-OH-progesterone, etc.) – Blood tests at different ages measure pituitary and gonadal hormones. In this syndrome, high LH and FSH with very low sex steroids and low anti-Müllerian hormone suggest primary gonadal failure and complete gonadal dysgenesis.
11. General blood tests and metabolic screen – Basic tests (full blood count, liver and kidney function, electrolytes, blood sugar) help rule out other illnesses and prepare for imaging or surgery. Metabolic screening can be added if there is doubt about other syndromic or metabolic conditions.
12. Targeted genetic testing for HHAT and DSD gene panels – Next-generation sequencing can directly look for disease-causing variants in HHAT and other genes known to cause DSD. Finding a pathogenic HHAT variant in a person with the clinical features confirms the diagnosis.
13. Broader exome or genome sequencing – In some patients, doctors may order exome or genome sequencing when a targeted panel is negative or when the clinical picture is unclear. This can find new or rare variants and sometimes expands the known spectrum of this syndrome.
14. Gonadal biopsy and histology – If surgery is done to remove streak gonads (often to prevent tumor risk), tissue is examined under the microscope. Histology typically shows dysgenetic or streak gonadal tissue, which confirms complete gonadal dysgenesis in a 46,XY individual.
Electrodiagnostic tests
15. Electroencephalogram (EEG) – EEG records the brain’s electrical activity. It is used when seizures are present or suspected. In this syndrome, EEG helps classify the seizure type, guides treatment choices, and monitors how well antiepileptic medicines are working.
16. Electromyography (EMG) and nerve conduction studies (if needed) – When there is significant muscle weakness or delayed motor development, EMG and nerve conduction tests can be used to check if nerves and muscles are working properly. While not specific for this syndrome, these tests can exclude additional neuromuscular diseases.
Imaging tests
17. Skeletal survey X-rays – A full set of X-rays of the skull, spine, chest, pelvis, arms, and legs is central in diagnosing skeletal dysplasias. In this syndrome, radiographs show generalized chondrodysplasia, broad long bones, abnormal pelvis, and a characteristic thorax shape.
18. Pelvic and abdominal ultrasound – Ultrasound can look for internal reproductive organs and gonads. In 46,XY individuals with this syndrome, gonads may be absent or streak-like, and the uterus and other Müllerian structures may or may not be present depending on hormone exposure in early life.
19. MRI of pelvis and gonads – MRI gives a more detailed picture of pelvic organs and any gonadal tissue than ultrasound. It helps surgeons and endocrinologists understand the anatomy before planning any surgery or further interventions.
20. MRI of brain and spine – MRI of the head often shows a small brain (microcephaly) and reduced size of the cerebellar vermis. These findings support the diagnosis when seen together with skeletal and DSD features, and they guide neurologists in planning seizure and developmental care.
Non-pharmacological treatments (therapies and other supports)
1. Multidisciplinary specialist clinic care
Children benefit when orthopaedic surgeons, endocrinologists, geneticists, urologists, psychologists, physiotherapists, and nurses work together in one plan. This team reviews growth, bones, breathing, heart, hormones, and gonads. [6] Regular team meetings help avoid conflicting decisions and support the family in choosing timing of surgeries, hormone therapy, and schooling.
2. Early physiotherapy and stretching
Physiotherapy keeps joints moving and muscles strong. Gentle stretches, positioning, and play-based exercises reduce contractures and stiffness caused by abnormal bones and joints. [7] Therapists teach parents safe ways to hold, move, and exercise their child at home to protect fragile bones and improve posture and balance.
3. Occupational therapy for daily activities
Occupational therapists help the child manage dressing, feeding, writing, and play despite short limbs or spinal curvature. [8] They may recommend adapted cutlery, special chairs, and bathroom aids. The goal is maximum independence and safety while avoiding over-strain on joints.
4. Orthopaedic bracing and supports
Braces for spine, knees, or ankles can improve alignment, reduce pain, and slow progression of deformity in growing bones. [9] Custom orthoses can support weak or misaligned joints during standing and walking, helping balance and reducing risk of falls and fractures.
5. Assistive mobility devices
Some children walk independently, others need walkers, crutches, or wheelchairs, especially for long distances. [10] Properly fitted devices reduce fatigue and protect joints. Mobility training gives the child confidence in school, outside play, and community life, while reducing caregiver lifting strain.
6. Respiratory physiotherapy and airway support
Chest shape changes and small rib cage can cause breathing problems. Respiratory physiotherapists teach breathing exercises, coughing techniques, and safe airway clearance. [11] Some children need oxygen, non-invasive ventilation, or sleep studies to detect night-time breathing issues early.
7. Speech and feeding therapy
If facial bones or palate are affected, sucking, chewing, or speech may be hard. Speech and feeding therapists guide safe swallowing, help prevent choking, and train clear speech sounds. [12] They may suggest special bottle teats or food textures to maintain good nutrition.
8. Nutritional and dietetic support
Dietitians check calorie, protein, calcium, and vitamin intake. Poor growth or feeding difficulties are common in complex skeletal dysplasia. [13] They design meal plans that support bone mineralisation, muscle strength, and healthy weight, and they help avoid both under-nutrition and obesity.
9. Developmental and educational support
Some children have normal learning, others need extra help. Early developmental assessment allows timely speech, cognitive, and behavioural interventions. [14] School plans can include extra time to move between classes, seating changes, assistive technology, and protection from bullying.
10. Psychological support and counselling
Differences in body shape and sex development can cause confusion, anxiety, and low mood in the child and family. Psychologists and counsellors provide age-appropriate explanations, coping strategies, and support for identity questions. [15] This support is essential during puberty and decision-making about surgeries or hormones.
11. Family and peer support groups
Meeting other families living with skeletal dysplasia or DSD helps reduce isolation. Support groups share practical tips about schooling, daily care, and navigating health systems. [16] They also give a safe space to talk about stigma and cultural challenges around sex development differences.
12. Non-drug pain management
Heat packs, gentle massage, hydrotherapy, and relaxation techniques can relieve chronic joint or back pain without relying only on medicines. [17] Physiotherapists and psychologists teach pacing, posture, and breathing methods to help the child stay active while managing discomfort.
13. Environmental adaptations at home
Simple changes like ramps, grab bars, lowered shelves, shower seats, and non-slip flooring make home safer and more accessible. [18] These adjustments prevent falls, reduce fracture risk, and support independence in washing, dressing, and toileting.
14. Fracture-prevention strategies
Because bones may be fragile, caregivers learn careful lifting, avoiding high-risk sports, and using protective gear. [19] Vitamin D, calcium, and weight-bearing activities under supervision also protect bone density, lowering the chances of fractures during everyday activities.
15. Regular tumour surveillance of gonads
Some DSD conditions carry a higher risk of gonadal tumours in dysgenetic or undescended gonads. [20] Regular ultrasound, MRI, and hormonal checks help decide the safest time for gonad removal or biopsy. This is a key part of long-term cancer prevention.
16. Gender identity and psychosocial support pathway
Decisions about sex of rearing and possible future gender identity must be slow, respectful, and led by the child as they grow. [21] DSD teams provide balanced information and support, avoid rushing irreversible steps, and keep mental health at the centre of care.
17. Genetic counselling for family planning
Genetic counsellors explain inheritance, carrier status, and recurrence risk in future pregnancies. [22] They discuss options such as prenatal diagnosis and pre-implantation genetic testing where legally and ethically available, helping families make informed decisions.
18. Prenatal and neonatal care planning
In subsequent pregnancies, high-risk obstetric teams can monitor fetal growth, bones, and genital development. [23] Plans for delivery at a tertiary centre with neonatal intensive care, orthopaedics, and endocrinology ensure early, coordinated support after birth.
19. Transition planning to adult services
As the child grows, the team prepares a written summary for adult clinics, covering bone status, surgeries, hormone history, fertility issues, and psychosocial needs. [24] Good transition reduces gaps in care and supports independent decision-making in adulthood.
20. Palliative and supportive care in severe cases
In very severe disease with major breathing or neurological problems, palliative care teams focus on comfort, symptom relief, and family support. [25] They help families talk about goals of care, home support, and end-of-life wishes in a compassionate, culturally sensitive way.
Drug treatments
(Important: No medicine is currently approved specifically to cure “chondrodysplasia with disorder of sex development syndrome”. Drugs are used for associated problems such as growth failure, bone fragility, hormone deficiency, pain, or seizures. Doses and timing must always follow official product labels and the child’s specialist.)
1. Recombinant human growth hormone (somatropin)
Somatropin injections are approved by the FDA for several causes of growth failure in children and adults. [26] In this syndrome, doctors may consider it if the child has proven growth hormone deficiency or another approved indication. It is usually given as a daily or weekly subcutaneous injection at bedtime. Side effects can include joint pain, headache, and rare glucose or hip problems.
2. Testosterone replacement therapy
For 46,XY individuals with male gender identity and low testosterone, injectable or oral testosterone products can induce and maintain puberty, muscle mass, and bone density. [27] Dosing is started low and slowly increased during adolescence. Possible side effects include acne, mood change, high red blood cells, and liver or cardiovascular risks, so monitoring is essential.
3. Estrogen replacement therapy
For individuals who will follow a female puberty pathway, transdermal or oral estradiol can support breast development, uterine growth, and bone health. [28] Treatment starts with very low doses and increases gradually. Side effects can include nausea, breast tenderness, and small increases in blood clot and stroke risk, especially with higher doses or other risk factors.
4. Cyclical progestin for uterine protection
If a person with a uterus receives estrogen, a progestin is often added in cycles to protect the endometrium from overgrowth and cancer. [29] Typical schedules use progestin for part of each month. Side effects can include mood changes, bloating, and irregular bleeding, so regimens are adjusted individually.
5. Vitamin D (ergocalciferol or cholecalciferol)
Vitamin D supplements help build strong bones and support calcium absorption, especially in skeletal dysplasia or limited sun exposure. [30] Depending on blood levels, doctors may use daily, weekly, or intermittent dosing. Too much vitamin D can cause high calcium, nausea, and kidney problems, so blood monitoring is important.
6. Active vitamin D analogs (calcitriol, doxercalciferol)
In some bone or kidney conditions, active vitamin D forms are needed to control calcium and parathyroid hormone levels. [31] These drugs are usually given orally in small daily doses. Over-treatment may lead to high calcium, itching, and vascular calcification, so doctors track calcium, phosphate, and kidney function regularly.
7. Calcium supplementation
Oral calcium (often with vitamin D) supports bone mineralisation when dietary intake is low. [32] Doses are spread through the day with meals to improve absorption. Excess calcium can cause constipation, kidney stones, or interfere with other medicines, so the goal is to reach, not exceed, recommended intake.
8. Bisphosphonates (for bone fragility)
Bisphosphonates such as alendronate are approved for osteoporosis and are sometimes used off-label in severe paediatric bone fragility to reduce fracture risk. [33] They slow bone resorption. Dosing regimens may be weekly oral tablets or periodic IV infusions. Side effects include stomach upset, bone pain, and very rare jaw or atypical fracture problems.
9. Simple analgesics (paracetamol / acetaminophen)
Paracetamol is widely used for mild to moderate pain and fever. It helps manage everyday joint and post-surgical pain with a good safety profile when dosing limits are respected. [34] Overdose can damage the liver, so families must follow weight-based instructions and avoid combining multiple products that contain paracetamol.
10. Non-steroidal anti-inflammatory drugs (NSAIDs)
NSAIDs like ibuprofen can relieve inflammatory joint or bone pain. They are often used for short periods after surgery or during painful flare-ups. [35] Side effects can include stomach irritation, kidney stress, and effects on blood clotting, so they are used carefully, especially in children with kidney or heart concerns.
11. Opioid analgesics (for severe pain)
For intense pain that does not respond to other measures, short-term opioid medicines such as morphine may be used in hospital or specialist care. [36] Doses are carefully titrated. Side effects include drowsiness, constipation, breathing suppression, and dependence, so doctors aim for the lowest effective dose and shortest duration.
12. Antiepileptic medicines
If a child develops seizures related to brain involvement, antiepileptic drugs (for example levetiracetam) may be prescribed to prevent fits and protect brain function. [37] Choice of medicine depends on seizure type and other health issues. Side effects can include tiredness, mood change, or rash, so careful follow-up is needed.
13. Muscle relaxants for spasticity (e.g., baclofen)
In cases with increased muscle tone and spasticity, oral or intrathecal baclofen can improve comfort, posture, and function. [38] Dosing is slowly increased to avoid excessive weakness or sleepiness. Sudden withdrawal must be avoided because it can cause serious rebound spasticity.
14. Inhaled bronchodilators
If chest deformity leads to airway narrowing or reactive airway disease, inhaled bronchodilators such as salbutamol may ease breathing and exercise tolerance. [39] They act quickly but can cause tremor, rapid heartbeat, or nervousness, especially at high doses. Spacers help children use inhalers correctly.
15. Glucocorticoid replacement (hydrocortisone)
In some DSD conditions with adrenal hormone problems, physiological doses of hydrocortisone replace missing cortisol and support blood pressure, glucose, and stress responses. [40] Doses are spread through the day and increased during illness or surgery. Long-term over-replacement can weaken bones and cause weight gain, so careful balancing is needed.
16. Gonadotropin-releasing hormone (GnRH) analogues
GnRH analogues can delay very early puberty, giving time for growth and psychosocial development, or they may be used as part of complex puberty management in DSD. [41] They are given as periodic injections or implants. Side effects may include hot flushes, mood swings, and reduced bone mineral density if used long term without sex-steroid add-back.
17. Antibiotics for recurrent infections
Children with chest wall problems or aspiration may have repeated pneumonias. Targeted antibiotics are used to treat proven bacterial infections based on local guidelines and cultures. [42] Overuse is avoided to prevent resistance. Preventive strategies such as vaccines and airway clearance are always combined with antibiotics.
18. Antiresorptive monoclonal antibodies (denosumab)
In selected older patients at very high fracture risk, denosumab, a monoclonal antibody that inhibits osteoclasts, may be considered following osteoporosis guidelines. [43] It is given as a subcutaneous injection at set intervals. Low calcium, infections, and rare jaw problems are important side effects, so monitoring is strict.
19. Hormonal contraceptives for cycle control
Combined hormonal contraceptives or progestin-only regimens can help regulate bleeding, manage pain, and provide contraception in individuals with a uterus. [44] Regimens are personalised to the person’s anatomy, hormones, and risk factors. Side effects include nausea, breast tenderness, and clot risk.
20. Topical skin treatments for ichthyosis or eczema
Some related chondrodysplasia syndromes have dry, scaly skin. Regular emollients, mild keratolytics, and anti-inflammatory creams can improve comfort and reduce infection risk. [45] Products are chosen to be gentle, fragrance-free, and suitable for long-term daily use.
Dietary molecular supplements
(Always check with the child’s doctors before starting any supplement, especially if there are kidney, liver, or hormonal problems.)
1. Calcium
Calcium is a key building block for bones and teeth. In skeletal dysplasia, reaching age-appropriate calcium intake through diet and, if needed, supplements helps maintain bone strength. [46] Doses are usually divided with meals. Too much calcium can cause constipation and kidney stones, so blood levels and kidney function must be checked.
2. Vitamin D3 (cholecalciferol)
Vitamin D3 helps the gut absorb calcium and supports proper mineralisation of bone. Supplementation aims to keep blood vitamin D in the target range for bone health. [47] Doctors choose daily or intermittent dosing based on age, diet, and sun exposure. Excess vitamin D can raise calcium too much, so monitoring is important.
3. Vitamin K2
Vitamin K2 helps activate proteins that bind calcium into bone rather than soft tissues. [48] In theory, this may support bone quality in skeletal disorders, although strong data in this specific syndrome are lacking. Usual doses are small daily capsules or drops; high doses can interact with blood-thinning medicines.
4. Omega-3 fatty acids
Omega-3 fats from fish oil or algae have anti-inflammatory effects that may support joint health and cardiovascular function. [49] Supplements are usually taken once or twice daily with food. They can cause mild stomach upset or fishy aftertaste and may slightly increase bleeding risk at high doses.
5. High-quality protein and amino acids
Adequate protein intake supports muscle strength, growth, and healing after surgery. [50] Sometimes dietitians suggest protein powders or amino acid supplements if appetite is low. Too much protein may strain kidneys, so balance and hydration are important.
6. Zinc
Zinc supports immune function, wound healing, and growth. [51] Supplementation may be used if blood levels are low or diet is poor. Typical doses are small daily tablets or syrups. High doses over time can upset the stomach and lower copper levels, so medical supervision is needed.
7. Magnesium
Magnesium helps muscles relax and participates in bone mineralisation and energy production. [52] Supplements are sometimes used if diets are low or blood levels are reduced. Too much magnesium can cause diarrhoea and, in kidney disease, dangerous heart rhythm changes, so dosing must be cautious.
8. Antioxidant vitamins (vitamin C and E)
Antioxidants support tissue repair and may reduce oxidative stress from chronic inflammation and surgeries. [53] They are usually obtained from fruits, vegetables, and nuts, but low-dose supplements can be added. Very high doses may cause stomach upset or interfere with other medicines, so “more” is not always better.
9. Probiotics and prebiotics
Gut health influences immunity and nutrient absorption. Probiotics (beneficial bacteria) and prebiotics (fibre that feeds them) may help children on frequent antibiotics or with feeding issues. [54] Products vary widely; doctors choose age-appropriate preparations and monitor for bloating or infection in very fragile patients.
10. L-carnitine
L-carnitine helps cells use fat for energy. Some children with complex chronic conditions take it to support energy levels, though high-quality data are limited. [55] Typical doses are divided through the day. Side effects can include fishy body odour or mild stomach upset, so families should discuss pros and cons with clinicians.
Immunity-supporting, regenerative, and stem-cell-related drugs
(Most of these are not specific treatments for this syndrome. Some are standard for other conditions; others remain experimental and may only be available in research settings.)
1. Routine vaccines and immune protection
The most important “immunity booster” is a full vaccine schedule, including influenza, pneumococcal, and COVID-19 vaccines, as advised locally. [56] Vaccines train the immune system to fight infections that could be dangerous in children with fragile bones, limited mobility, or lung problems.
2. Immunoglobulin replacement (in selected cases)
If separate immune defects are found, intravenous or subcutaneous immunoglobulin may be used to prevent serious infections. [57] It provides pooled antibodies from donors. Doses are usually every few weeks. Side effects can include headache, fever, and rare allergic reactions, so infusions are monitored closely.
3. Granulocyte colony-stimulating factor (G-CSF, filgrastim)
In patients with significant neutropenia from other causes, G-CSF can stimulate bone marrow to produce more white blood cells and reduce severe infections. [58] It is injected under the skin. Side effects include bone pain and, rarely, spleen enlargement. Use in this syndrome would be based only on proven marrow problems.
4. Recombinant growth hormone as regenerative therapy
Beyond height, somatropin may support muscle mass and bone turnover, acting as a “regenerative” hormone in people with proper indications. [59] Benefits must be weighed against risks like raised intracranial pressure and glucose intolerance. Long-term safety data come from other growth disorders, not this rare syndrome, so decisions are highly individual.
5. Bone-anabolic agents (teriparatide and similar, in adults)
In adults with severe osteoporosis, parathyroid hormone analogues like teriparatide can stimulate new bone formation and reduce fractures. [60] Treatment is usually limited to a defined period. Side effects include nausea, leg cramps, and transient calcium changes. These agents are not standard for children and would not be used without expert advice.
6. Experimental stem cell and gene-targeted therapies
Researchers are exploring mesenchymal stem cell therapies and gene-editing tools for some skeletal dysplasias and DSD-related genes such as SOX9 pathways. [61] These approaches remain experimental, are not routine care, and may only be available in clinical trials. Families should be cautious about unregulated “stem cell” clinics that lack solid scientific backing.
Surgical treatments
1. Corrective osteotomy and limb alignment surgery
Orthopaedic surgeons may cut and realign bones (osteotomy) to correct severe bowing, knock-knee, or rotational deformities that limit standing and walking. [62] Plates, screws, or external frames hold bones while they heal. The goal is better function, reduced pain, and prevention of future joint damage.
2. Spinal fusion or decompression
If spinal curvature or vertebral abnormalities cause instability, pain, or spinal cord compression, spinal fusion may be recommended. [63] Surgeons connect vertebrae with rods and bone grafts to stabilise the spine. In some cases, decompression is done to relieve pressure on nerves and prevent paralysis or bladder problems.
3. Limb lengthening procedures
Selected patients may undergo gradual limb lengthening using external or internal devices. [64] The aim is to improve limb symmetry and function, not to “normalise” appearance. These are long, intensive procedures with risks of infection, joint stiffness, and pain, so decisions must be careful and patient-centred.
4. Gonadectomy or gonadal biopsy
In some 46,XY DSD conditions, dysgenetic or undescended gonads carry a high risk of gonadal tumours such as gonadoblastoma. [65] Removing these gonads (gonadectomy) or sampling them (biopsy) reduces cancer risk. Timing depends on tumour risk, hormone needs, and the person’s age and wishes, and must be discussed in detail with the family.
5. Genital reconstruction or urogenital surgery
If there are urogenital anomalies that cause urinary obstruction, recurrent infections, or difficulties with hygiene, reconstructive surgery may be needed. [66] Decisions about appearance-focused genital surgery are now made very cautiously, aiming to delay irreversible procedures until the person can participate in decisions whenever possible.
Prevention of complications
Because this syndrome is genetic, we cannot prevent it completely, but we can prevent many complications.
Pre-conception genetic counselling and carrier testing – helps parents understand recurrence risk and consider options like prenatal or pre-implantation genetic diagnosis. [67]
Early diagnosis after birth – quick referral to genetics, orthopaedics, and endocrinology allows monitoring and early treatment of breathing, feeding, and gonadal issues. [68]
Complete immunisation schedule – reduces risk of serious chest and bloodstream infections in children with fragile lungs and bones. [69]
Routine gonadal tumour surveillance and timely gonadectomy – prevents malignant transformation in high-risk dysgenetic gonads. [70]
Bone health optimisation (diet, vitamin D, safe exercise) – lowers fracture risk and supports mobility across life. [71]
Safe environment and fall prevention – home adaptations, suitable footwear, and supervised play reduce falls and injuries. [72]
Regular growth, spine, and limb monitoring – timely X-rays and clinic checks catch deformities early, when bracing or smaller surgeries are more effective. [73]
Psychological support and anti-bullying strategies – protects mental health and reduces long-term anxiety and depression. [74]
Planned transitions (child to teen to adult services) – avoids gaps in medicine supply, hormone management, and surveillance during key life stages. [75]
Reliable information and avoidance of unproven therapies – prevents harm from unregulated stem-cell clinics, extreme diets, or miracle cures not backed by evidence. [76]
When to see doctors
Families should seek medical help urgently if the child has difficulty breathing, blue lips, high fever, repeated vomiting, seizures, or sudden severe pain in back, neck, or limbs. These may signal dangerous chest infections, spinal cord compression, or other emergencies. [77]
Non-urgent but important reasons to see the specialist team include slower growth than expected, new or worsening limb deformity, pain that limits sleep or play, feeding problems, or delayed or very early puberty. [78] Families should also contact doctors if genital appearance changes, lumps appear in the groin or abdomen, or there is blood in urine or stool, as these may relate to gonadal or urinary issues.
Regular planned check-ups with orthopaedics, endocrinology, and genetics are just as important as emergency visits. They allow the team to adjust braces, hormone therapy, supplements, and surveillance plans before crises happen. [79]
What to eat and what to avoid
Eat calcium-rich foods – such as dairy products, fortified plant milks, tofu set with calcium, and small bony fish, to support bones. [80]
Include vitamin-D-rich options – fortified foods and safe sunlight exposure, plus prescribed supplements where needed, to aid calcium absorption. [81]
Focus on protein – lean meats, eggs, lentils, beans, and nuts help maintain muscle strength, especially when mobility is limited. [82]
Add plenty of fruits and vegetables – colourful produce provides antioxidants, fibre, and vitamins that support immunity and healing. [83]
Drink enough water – good hydration helps bowel function, kidney health, and general wellbeing, especially when taking calcium or other medicines. [84]
Avoid very salty processed foods – excessive salt can worsen blood pressure and burden the heart and kidneys. [85]
Limit sugary drinks and sweets – these add calories without nutrients, increase obesity risk, and may worsen bone and joint pain. [86]
Be careful with high-dose unproven supplements – mega-doses of vitamins, minerals, or herbal products may harm kidneys, liver, or interact with medicines. [87]
Avoid regular fast food and deep-fried snacks – they are high in unhealthy fats and salt, which do not support long-term heart and bone health. [88]
Avoid alcohol and smoking exposure – for older teens and adults, this means not using these products; for children, it means a smoke-free home, because smoke harms lungs and bone health. [89]
Frequently asked questions (FAQs)
1. Is there a cure for chondrodysplasia with disorder of sex development syndrome?
At present there is no cure that corrects the underlying gene change. [90] Treatment focuses on growth support, bone protection, DSD management, and quality of life. Research into gene-targeted and regenerative therapies is ongoing but still experimental.
2. How is the diagnosis confirmed?
Doctors combine clinical examination, X-rays, hormone tests, and detailed genetic testing, often using exome or panel sequencing that includes HHAT and other DSD-related genes. [91]
3. Will every child have the same severity?
No. Even with the same gene, bone changes, height, breathing problems, and DSD features can vary widely between patients. [92]
4. Can my child have a “normal” life expectancy?
Some children with milder skeletal and respiratory involvement may live into adulthood, especially with good supportive care. Severe chest and spine problems can reduce life expectancy, so early respiratory and orthopaedic management is vital. [93]
5. How are decisions about sex of rearing made?
Teams look at chromosomes, gonads, hormone production, internal anatomy, potential fertility, and family values. [94] They discuss options openly and avoid rushing irreversible steps, aiming to respect the child’s future autonomy.
6. Can fertility be preserved?
Fertility is often reduced because of gonadal dysgenesis or early gonadectomy, but some patients may have partial fertility options. [95] Fertility specialists can discuss semen, oocyte, or embryo preservation in suitable cases.
7. Are hormone treatments lifelong?
If the body cannot produce enough sex hormones or other key hormones, replacement is usually lifelong, with doses adjusted as the person ages. [96]
8. What are the main risks of hormone therapy?
Risks depend on the hormone: growth hormone can affect glucose and hip joints; testosterone can raise blood counts; estrogen can increase clot risk. [97] Careful monitoring aims to balance benefits and risks.
9. How often will my child need X-rays or scans?
Frequency depends on age and severity. Many children need periodic X-rays of spine and limbs, and ultrasound or MRI of gonads. [98] Doctors try to keep imaging to the minimum needed to guide safe care.
10. Will surgery always be necessary?
Not always. Some children manage well with physiotherapy, bracing, and medical treatment. Surgery is considered when deformity or gonadal risk clearly harms health or function. [99]
11. Can my child play sports?
Many children can join adapted physical activities such as swimming, cycling with support, or gentle games. [100] Contact sports and high-impact activities may not be safe, especially with severe bone fragility or spinal issues.
12. How can we support our child’s mental health?
Open, age-appropriate communication, contact with peers who have similar conditions, and regular psychological support help a lot. [101] School staff should be informed to prevent bullying and support inclusion.
13. Should we join a registry or research study?
Many teams encourage joining rare disease registries and ethically approved research. [102] This can improve understanding of the condition and may give earlier access to new tests or treatments, but participation is always voluntary.
14. What questions should we ask at clinic visits?
Families can ask about growth trends, bone status, hormone levels, tumour risk, planned imaging, school support, and mental health. [103] Keeping a written question list helps use clinic time well.
15. Where can we find reliable information?
Reliable sources include national rare disease centres, peer-reviewed articles, and recognised patient organisations for skeletal dysplasia and DSD. [104] Health professionals can point to websites and booklets written in clear language and updated regularly, rather than social media rumours.
Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, geological location, weather and previous medical history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. Regular check-ups and awareness can help to manage and prevent complications associated with these diseases conditions. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. We always try to ensure that the content is regularly updated to reflect the latest medical research and treatment options. Thank you for giving your valuable time to read the article.
The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members
Last Updated: January 13, 2026.
