FAM111A-Related Skeletal Dysplasias

Clinical characteristics: FAM111A-related skeletal dysplasias include the milder phenotype of Kenny-Caffey syndrome (KCS) and a more severe lethal phenotype, osteocraniostenosis (OCS). KCS is characterized by proportionate short stature (typically postnatal onset), relative macrocephaly, large anterior fontanel with delayed closure, characteristic facial features, cortical thickening of the long bones with stenosis of the medullary cavity, and ophthalmologic and dental manifestations. OCS is characterized by intrauterine growth deficiency, microcephaly, characteristic facial features, decreased skull ossification, slender long bones with cortical thickening, stenosis of the medullary cavity of the long bones, flared metaphyses, and thin ribs with thoracic and pulmonary hypoplasia leading to respiratory insufficiency. Perinatal fractures may occur. Primary hypoparathyroidism with hypocalcemia and hyperphosphatemia can occur in individuals with KCS and OCS.

Diagnosis/testing: The diagnosis of a FAM111A-related skeletal dysplasia is established in a proband with suggestive findings and a heterozygous pathogenic variant in FAM111A identified by molecular genetic testing.

Management: Treatment of manifestations: Survivors with OCS require aggressive respiratory support and management of restrictive lung disease with a respiratory specialist; for all affected individuals, supplemental calcium and activated forms of vitamin D per endocrinologist; management of refractive errors and cataracts; management of dental manifestations with a dental specialist / oral surgeon; environmental and/or occupational modifications as needed for short stature in those with KCS; conservative or surgical management per orthopedist and/or neurosurgeon for scoliosis; individualized developmental support by allied health clinicians; referral to psychologist as needed.

Surveillance: For individuals with KCS and OCS, assess anthropometry (height, weight, growth velocity, limb proportions, and upper-to-lower segment proportions) at each visit; clinical examination for scoliosis at each visit, with referral to orthopedics and physical therapy as necessary; assess functional limitations and assessment with physical therapy and/or occupational therapy as needed; measurement of serum calcium, phosphate, and vitamin D every three months until calcium level is normalized on treatment and then subsequently every six months; clinical examination for manifestations of hypocalcemia; abdominal ultrasound to assess for nephrocalcinosis and/or nephrolithiasis annually while on treatment; ophthalmology examination annually or as indicated; dental examinations every six months; assess for clinical manifestations of anemia at each visit; monitor developmental progress and educational needs at each visit throughout childhood; assess for changes in mood, affect, and/or psychosocial stressors at each visit; assess care coordination needs and genetic counseling needs at each visit.

Genetic counseling: FAM111A-related skeletal dysplasias (including KCS and OCS) are autosomal dominant disorders.

1. KCS. Most individuals diagnosed with KCS have the disorder as the result of a de novo FAM111A pathogenic variant. Rarely, individuals diagnosed with KCS have an affected parent. If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Each child of an individual with KCS has a 50% chance of inheriting the FAM111A pathogenic variant.

2. OCS. With one possible exception, all probands reported to date with OCS whose parents have undergone molecular genetic testing have the disorder as the result of a de novo FAM111A pathogenic variant. Given that probands with OCS typically have the disorder as the result of a de novo FAM111A pathogenic variant, the risk to other family members is presumed to be low.

Once the FAM111A pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.