Dr Theresa Raju, Dr Sajitha Nair, Dr Sindhu, Dr Sreya, Dr Sheena Kochumon (paediatric genetics), Dr C Jayakumar, Amrita Institute of Medical Sciences
Eleven year-old female child with history of recurrent episodes of cough with wheeze on controllers presented with short stature, failure to thrive, and history recurrent (5)fractures following trivial trauma in the past.
First born of a non – consanguineous parentage was born after 3 years of infertility treatment. Mother had varicella 2 weeks prior to delivery. Delivery was normal
Frontal bossing was noticed at 6months of age. At 1 year of age following a trivial fall fracture of clavicle occurred
She also had 4 episodes of tibial fracture following trivial trauma requiring cast for 6 weeks each.
Irrespective of phosphorous ALP and normal parathormone
she was treated as rickets, due to large head, delayed closure of AF, frontal bossing and low 25-OH vitamin D3 levels. Child received Vitamin D supplements three times as injection as well as oral supplements. Child also had recurrent episodes of cough with wheeze for which she was on fluticasone salmetrol combination
She was consulted for orthodontics
in view of narrow and high arched palate.
Currently studying in 7thstandard with good scholastic performance. She is immunized for age according to NIS schedule.
Family history: Younger sibling is a known case of multi trigger wheezer
No history of any frequent fractures for any of the family members
At admission, vitals were stable
No Pallor, icterus, cyanosis, clubbing, lymphadenopathy, edema
Auxology: Wt-26kg(at -3SD), Ht:131cm (<-3SD), BMI:15.2(between 0 and -2SD), Head circumference:49cm
Mid parental height: 157.5cm, US:LS ration: 0.9:1. SMR stage :3
Head to foot examination: long face, prominent nose, high arched narrow palate, microretrognathia, hyperelastic fingers, turricephaly, broad forehead, brachydactyly of fingers and toes, flat foot and scoliosis
Systemic examination was within normal limits.
Counts did were normal.
Vitamin D level was low with normal calcium, phosphorous, ALP and PTH. RFT,LFT,Serum electrolyes, TFT and URE were normal. IgElevels were elvated(8321IU/ml).
Her bone age was corresponding to chronological age, USG Abdomen with pelvis was normal. ECHO did not reveal any structural abnormality.
As Xray of limbs showed generalized osteosclerosis, previous xrays were reviewed pediatric radiologist. It was reported as generalized osteosclerosis with narrowed medullary cavity and changes were more pronounced in the appendicular skeleton.
Xray skull showed widened calvarial sutures along with multiple Wormian bones. There was doubtful acroosteolysis in the terminal phalanges and lateral clavicular head. Xray foot done showed acroosteolysis.
In view of short stature, multiple factures and xray showing osteosclerosis and doubtful acro osteolysis, a possibility of pycnodysostosis was considered. Pediatirc genetic consultation was availed and whole exome sequencing was done which showed pycnodysostosis.
Parents were counselled about the diagnosis and the need for multidisciplinary follow up.
DISCUSSION:
Pycnodysostosis is a rare autosomal recessive genetic disorder due to an impaired degradation of the organic matrix of bone osteoclasts. It is caused loss of function mutations of the cathepsin K (CTSK) gene. CTSK is responsible for the degradation of collagen type 1 at low Ph.It is characterized short stature, increased radiodensity of bone, persisting open cranial sutures, obliquity of mandibular angle and defects of terminal phalanges of fingers.
Findings:
Clinical: short limbed short stature, brachydactyly, frontal bossing, persistently open anterior fontanelle, prominent nose with convex nasal bridge, midface retrusion and small jaw, OSA, prominent eyes and nose, high arched palate/grooved palate, nail anomalies (dysplastic, grooved, flattened)
Radiographic findings: generalized progressive osteosclerosis, acro osteolysis of terminal phalangs, non-pneumatizedmastoids, delayed fusion of cranial sutures, increased incidence of fractures, clavicular dysplasia, congenital pseudoarthrosis of clavicle.
Lab findings: Normal serum calcium, phosphorous, vitamin D and ALP. Growth hormone deficiency, low IGF-1
Diagnosis: It can be established in a proband with characteristic clinical and radiographic features and/or biallelic pathogenic variants in CTSK identified molecular genetic testing.
Management: Growth hormone therapy, environmental or occupational modifications as needed. Orthopedicmanagement of fractures and scoliosis, craniofacial and neurosurgical management as required for cleft palate, craniosynostosis, maxillary and mandibular hypoplasia.
Genetic counselling: If both parents are known to be heterogeneous for a CTSK pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier and a 25% chance of being unaffected and not a carrier. Once the CTSK pathogenic variants have been identified in an affected family member, carrier testing for at risk relatives, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
