Congenital NAD Deficiency Disorder

Clinical characteristics: Congenital NAD deficiency disorder (CNDD) is a multisystem condition in which cardiac, renal, vertebral, and limb anomalies are common, mimicking the clinical features described in VACTERL association. Congenital heart defects can include left-sided heart lesions, right-sided heart lesions, or both. Almost all surviving individuals have short stature, many with disproportionately shortened limbs. Vertebral anomalies, including hemivertebrae and vertebral fusion, occur frequently, often with rib anomalies. Renal anomalies may be severe, including dysplasia/hypoplasia and renal agenesis. Developmental delay / intellectual disability has been reported in more than half of affected individuals, although some affected individuals have had normal development, and some individuals succumbed to their congenital anomalies before developmental assessment could be performed. Other less common features may include cleft palate, eye anomalies, sensorineural hearing loss, tracheoesophageal fistula, polysplenia, anteriorly displaced anus, tethered spinal cord, cystic hygroma, epilepsy, hypothyroidism, and hypoparathyroidism.

Diagnosis/testing: The diagnosis of CNDD is established in a proband with suggestive findings and biallelic pathogenic variants in HAAO, KYNU, or NADSYN1 identified by molecular genetic testing.

Management: Treatment of manifestations: There is no cure for CNDD. Supportive care includes standard treatment for congenital anomalies (congenital heart defects, cleft palate, limb anomalies, scoliosis, tethered spinal cord, renal anomalies, tracheoesophageal fistula / pyloric stenosis / laryngeal web, polysplenia, and strabismus/ptosis) and for functional/medical issues (hearing loss, developmental delay / intellectual disability, epilepsy, hypothyroidism, and hyperparathyroidism).

Surveillance: At each visit: measurement of growth parameters; evaluation of nutrition status and safety of oral intake; assessment of mobility and self-help skills; monitoring of developmental progress and educational needs; monitoring of seizures; and assessment for new manifestations, such as changes in tone. At each visit until skeletal maturity: monitoring for scoliosis. Annually or as clinically indicated: audiology evaluation; ophthalmology evaluation; assessment of thyroid function; and serum calcium levels in those with hypoparathyroidism. For those with renal anomalies: measurement of blood pressure at each visit and renal function tests annually or as clinically indicated.

Agents/circumstances to avoid: Avoidance of medications that impair kidney function, in those with renal aplasia (solitary kidney) and/or known impaired kidney function.

Genetic counseling: CNDD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CNDD-related 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 CNDD-related pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.