Abstract Details

Title Congenital Contractures of the Limbs and Face, Hypotonia, and Developmental Delay (CLIFAHDD) Syndrome: Case Series and Systematic Review

Topic Child Neurology and Developmental Neurology

Presentation(s) P4 - Poster Session 4 (8:00 AM-9:00 AM)

Poster/Presentation
Number 8-008

Objective

Compile and analyze the clinical features associated with CLIFAHDD across reported cases.

Background

Congenital Contractures of the Limbs and Face, Hypotonia, and Developmental Delay (CLIFAHDD) is a rare neurodevelopmental disorder caused by pathogenic variants in the NALCN gene. While hallmark neurologic and musculoskeletal features are recognized, the broader multisystem clinical spectrum remains incompletely characterized.

Design/Methods

Four individuals with CLIFAHDD were clinically characterized. A systematic review of molecularly confirmed cases was performed using different databases. Inclusion criteria required individuals with confirmed NALCN mutations. Data from 102 total individuals were extracted. Features were classified as primary (coverage ≥20 patients, frequency ≥70%) or supportive (coverage ≥10 patients, frequency ≥50%). Percentages reflect only patients in whom the feature was assessed.

Results Clinical evaluations of four unique patients revealed features of CLIFAHDD: global neurodevelopmental delay, hyperkinetic movements, ASD, irregular breathing, disrupted sleep, recurrent vomiting, and clinical regression with progressive ataxia. In the systematic review, findings included hypotonia (85%,n=44/52), global neurodevelopmental delay (100%,n=69/69), distinct craniofacial features—nasal abnormalities (98%,n=41/42), long philtrum (86%,n=24/28), micrognathia (87%,n=27/31), full cheeks (92%,n=22/24); and musculoskeletal contractures such as distal arthrogryposis (79%,n=37/47), camptodactyly (100%,n=36/36), ulnar deviation (100%,n=34/34), and clubfoot (67%,n=47/70). Neonatal complications included ventilatory support (42%,n=14/33), ICU care (53%,n=19/36), and feeding difficulties (81%,n=30/31). Neurologic features included movement disorders (75%,n=46/61), strabismus (65%,n=28/43), seizures (43%,n=23/53), autonomic dysfunction (90%,n=43/48), and ASD (34%,n=17/50). Gastrointestinal symptoms included feeding difficulties (92%,n=24/26), GERD (76%,n=41/54), constipation (76%,n=48/63), and recurrent vomiting (75%,n=27/36). Respiratory findings included irregular breathing (63%,n=24/38), respiratory insufficiency (47%,n=27/58), ventilatory support (24%,n=8/34), and central (38%,n=16/42) and obstructive (41%,n=17/42) apneas. Sleep disturbances included nocturnal arousals (54%,n=19/35) and other sleep issues (46%,n=26/56). Brain MRI was abnormal in 60% (n=30/50), with >90% showing cerebellar and cerebral atrophy.

Conclusions

CLIFAHDD is a complex multisystem disorder. Broader recognition of non-neurologic manifestations is essential for comprehensive care and highlights the need for longitudinal, standardized phenotyping to guide future management and interventions.

Authors/Disclosures
S. Azareli Garcia Velazquez, MD PRESENTER	Dr. Garcia Velazquez has nothing to disclose.
Paloma Parra-Díaz, MD	Dr. Parra-Díaz has nothing to disclose.
Burak Altintas, MD	Dr. Altintas has nothing to disclose.
Nawale Hadouiri, MD, PhD	Dr. Hadouiri has nothing to disclose.
Emily L. Durham, PhD	Dr. Durham has received personal compensation in the range of $50,000-$99,999 for serving as a Director with The TBCK Foundation. Dr. Durham has received personal compensation in the range of $10,000-$49,999 for serving as a Manager with The Channeling Hope Foundation.
Cédric Martin	Mr. Martin has received personal compensation for serving as an employee of Roche Pharma AG. Mr. Martin has stock in Biotest AG. Mr. Martin has stock in Gilead Sciences. Mr. Martin has stock in Medtronic plc. Mr. Martin has stock in Roche Holding AG.
Arnaud Monteil, PhD	Dr. Monteil has nothing to disclose.
Catherine Gooch, MD	Dr. Gooch has nothing to disclose.
Antonio Gil-Nagel, MD (Hospital Ruber Internacional)	Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biocodex. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EISAI . Dr. Gil-Nagel has received personal compensation in the range of $0-$499 for serving as a Consultant for GW Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Angelini Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EISAI. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for GW Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for PTC Therapeutics . Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Stoke . Dr. Gil-Nagel has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Zogenix . Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Angelini Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for BIAL . Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for EISAI . Dr. Gil-Nagel has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for GW Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Jazz Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for PTC Therapeutics . Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for UCB Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Zogenix . The institution of Dr. Gil-Nagel has received research support from Jazz Pharmaceuticals. The institution of Dr. Gil-Nagel has received research support from PTC Therapeutics. The institution of Dr. Gil-Nagel has received research support from Zogenix. The institution of Dr. Gil-Nagel has received research support from Agencia Estatal Innovacion.
Daniel Calame, MD, PhD (Baylor College of Medicine, Child Neurology)	Dr. Calame has nothing to disclose.
Jeremy Tanner, MD (UTHSA - Neurology)	An immediate family member of Dr. Tanner has received personal compensation for serving as an employee of Channeling Hope Foundation. The institution of Dr. Tanner has received research support from NIA, NINDS. Dr. Tanner has a non-compensated relationship as a Chief Scientific Officer with Channeling Hope Foundation that is relevant to AAN interests or activities.

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