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vertebral, cardiac, renal, and limb defects syndrome 2 (VCRL2) - Clinical Profile, Genes & Research | Kisho | Kisho

Organ System	Phenotype Count	Example Features
Kidneys and urinary system	3	Renal hypoplasia, Unilateral renal agenesis, Chronic kidney disease
Brain and nerves	2	Delayed speech and language development, Depressed nasal bridge
Bones and joints	1	Vertebral segmentation defect
Head and neck	1	Microcephaly
Growth and development	1	Short stature
Heart and blood vessels	1	Hypoplastic left heart
Lab test results	1	Elevated circulating 3-hydroxykynurenine concentration

GeneReviews

Clinical Guidance

Congenital NAD deficiency disorder (CNDD) is a multisystem condition in which cardiac, renal, vertebral, and limb anomalies are common. Short stature with shortened long bones, developmental delay/ intellectual disability, and other organ system involvement may also be present . The morbidity and mortality of these anomalies can be quite variable. To date, 27 individuals have been identified with biallelic pathogenic variants in HAAO, KYNU, or NADSYN1, of which 16 are still living [; ; ; ; ; ; ; ; Authors, personal observation]. The following description of the phenotypic features associated with this condition is based on these reports. Table 2. Congenital NAD Deficiency Disorder: Frequency of Select Features

Feature	Proportion of Persons w/Feature1	Comment
Congenital heart defects	25/25 (100%)	Both left- right-sided heart defects have been described.
Short stature	12/13 (92%)	—
Vertebral anomalies	18/26 (69%)	—
Developmental delay/ intellectual disability	8/13 (62%)	—
Renal anomalies	16/27 (59%)	—
Facial dysmorphisms	12/26 (46%)	—
Shortened limbs	10/27 (37%)	—
Limb anomalies	7/24 (29%)	Hyperphalangism, short finger phalanges, absent toes, right terminal transverse upper limb reduction, radioulnar synostosis
Microcephaly	7/24 (29%)	Incl 2 persons w/small brain on autopsy
Neuromuscular anomalies	6/27 (22%)	Talipes, arthrogryposis, pterygia
Sensorineural hearing loss/ inner ear abnormalities	4/27 (15%)	—
Other brain findings	4/27 (15%)	—
Syndactyly	4/26 (15%)	—
Nuchal redundancy/ cystic hygroma	4/26 (15%)	Noted either on prenatal imaging or postnatal physical exam 1. Cardiovascular anomalies. Structural heart defects have been reported in all affected individuals thus far. Hypoplastic left heart (8 individuals) and tetralogy of Fallot (3 individuals) were the most common.

Source: GeneReviews — "Congenital NAD Deficiency Disorder"

Diagnosis

Drawn from GeneReviews diagnostic guidelines, newborn screening panel status (RUSP), and ClinGen gene-disease validity classifications. Reflects current clinical evidence and consensus where available.

GeneReviews

Diagnostic Criteria

No consensus clinical diagnostic criteria for congenital NAD deficiency disorder (CNDD) have been published. However, the spectrum of congenital anomalies may overlap with the clinically described VACTERL association (vertebral anomalies, anal anomalies, cardiac defects, tracheoesophageal fistula with esophageal atresia, renal anomalies, and limb anomalies).

Suggestive Findings

CNDD should be suspected in individuals with the following imaging findings, further clinical features, and family history.

Imaging findings

Source: GeneReviews — "Congenital NAD Deficiency Disorder"

GeneReviews

Differential Diagnosis

Many of the congenital anomalies seen in congenital NAD deficiency disorder (CNDD) can be seen as isolated anomalies in an otherwise unaffected individual. VACTERL association (vertebral defects, anal atresia, cardiac malformation, tracheoesophageal fistula with esophageal atresia, renal anomalies, and limb anomalies). Vertebral, cardiac, renal, and limb anomalies are common in both CNDD and VACTERL association . However, anal anomalies and tracheoesophageal fistula are rarely reported in CNDD. In addition, CNDD is frequently associated with disproportionate short stature, and developmental delays/ intellectual disability and facial dysmorphisms are more common in CNDD than in VACTERL association. Disorders of known genetic cause in the differential diagnosis of CNDD are summarized in . Table 3. Genetic Disorders in the Differential Diagnosis of Congenital NAD Deficiency Disorder

Gene/Genetic Mechanism	Disorder	MOI	Overlapping Features	Distinguishing Features

Genetic testing for KYNU is available. Testing is considered confirmatory for diagnosis.

Biomarker and diagnostic research for vertebral, cardiac, renal, and limb defects syndrome 2 has been reported in the published literature.

Treatment

Compiled from FDA-approved drug records, orphan drug designations, and FDA Adverse Event Reporting System (FAERS) safety data. GeneReviews management guidance is included where available.

No approved treatments are currently available for vertebral, cardiac, renal, and limb defects syndrome 2. The disease remains an area of unmet medical need.

GeneReviews

Management Guidelines

No clinical practice guidelines for congenital NAD deficiency disorder (CNDD) have been published. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with CNDD, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 4. Congenital NAD Deficiency Disorder: Recommended Evaluations Following Initial Diagnosis

System/Concern	Evaluation	Comment
Constitutional	Measurement of weight, length/height, head circumference	To assess for short stature /or microcephaly
Craniofacial	Physical exam for evidence of cleft palate or other craniofacial findings	Referral to craniofacial clinic, ENT, or plastic surgeon as appropriate
Hearing	Audiology eval	To assess for hearing loss
Musculoskeletal	AP lateral radiographs of entire spine	To assess for vertebral rib anomalies Assessment for clubfoot, arthrogryposis, pterygia, limb reduction defects, syndactyly
Cardiovascular	Echocardiogram	To assess for congenital heart defects

Source: GeneReviews — "Congenital NAD Deficiency Disorder"

GeneReviews

Clinical Guidance

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

Source: GeneReviews — "Congenital NAD Deficiency Disorder"

GeneReviews

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Congenital NAD Deficiency Disorder"

Clinical Trials

View trials for vertebral, cardiac, renal, and limb defects syndrome 2

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Prognosis

Based on GeneReviews surveillance recommendations, HPO phenotype frequency and severity annotations, and published prevalence estimates from Orphanet and OMIM.

GeneReviews

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 6. Congenital NAD Deficiency Disorder: Recommended Surveillance

System/Concern	Evaluation	Frequency
Hearing	Audiology eval	Annually in childhood or as clinically indicated
Musculoskeletal	Clinical assessment for scoliosis	At each visit until skeletal maturity Physical medicine, OT/PT assessment of mobility, self-help skills
Renal	Measurement of blood pressure	At each visit for those w/known renal anomalies Renal function tests incl serum BUN/creatinine urinalysis
Development	Monitor developmental progress educational needs.	At each visit Neurologic
Endocrinologic	Assessment of thyroid function1	As clinically indicated Assessment of serum calcium levels
Eyes	Ophthalmology eval	Annually or as clinically indicated
Family/Community	Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).	At each visit BUN = blood urea nitrogen; OT = occupational therapy; PT = physical therapy 1. Which may include obtaining thyroid-stimulating hormone and free thyroxine levels.

Source: GeneReviews — "Congenital NAD Deficiency Disorder"

Phenotype severity distribution: 3 always present features, 16 common features.

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vertebral, cardiac, renal, and limb defects syndrome 2

Overview

Clinical Presentation

Clinical Guidance

Explore clinical features

Genetic Landscape

Clinical Guidance

Diagnosis

Diagnostic Criteria

Suggestive Findings

Differential Diagnosis

Treatment

Management Guidelines

Clinical Guidance

Therapies Under Investigation

Clinical Trials

Prognosis

Surveillance Guidelines

Research Landscape

Recent Publications

Medical References

External Resources

OMIM

GARD

Questions for Your Care Team

Questions for Your Care Team

vertebral, cardiac, renal, and limb defects syndrome 2

Overview

Clinical Presentation

Clinical Guidance

Explore clinical features

Genetic Landscape

Clinical Guidance

Diagnosis

Diagnostic Criteria

Suggestive Findings

Differential Diagnosis

Treatment

Management Guidelines

Clinical Guidance

Therapies Under Investigation

Clinical Trials

Prognosis

Surveillance Guidelines

Research Landscape

Recent Publications

Medical References

External Resources

OMIM

GARD

Related Diseases

Questions for Your Care Team

Questions for Your Care Team