Hedgehog acyl‐transferase‐related multiple congenital anomalies: Report of an additional family and delineation of the syndrome

Abstract

This study includes previous reports of four affected individuals from two unrelated families with hedgehog acyl-transferase (HHAT)-related multiple congenital anomaly syndrome. Microcephaly, small cerebellar vermis, holoprosencephaly, agenesis of corpus callosum, intellectual disability, short stature, skeletal dysplasia, microphthalmiaanophthalmia, and sex reversal constitute the phenotypic spectrum of this condition with variable expression. We report an additional family with three affected conceptuses: two abortuses and one living proband. We did proband-parents trio exome sequencing and identified a biallelic in-frame deletion c.365_367del; (p.Thr122del) in exon 5 of HHAT. With this report, we delineate the phenotype and allelic heterogeneity of the HHAT-related multiple congenital anomaly syndrome.

Muscle spasms as presenting feature of Nivelon‐Nivelon‐Mabile syndrome

“…The proband was concluded to be affected with HHAT gene‐associated NNMS in view of these results and concordance with previously reported phenotype of this condition (Abdel‐Salam et al, 2019; Callier et al, 2014; Mazen et al, 2022; Pande et al, 2021).…”

“…This case shows many concordant findings to previous patients like microcephaly, intellectual disability, muscle spasms, elevated serum creatine phosphokinase, short stature, and brachydactyly. However, some previously reported features, namely, central nervous system (CNS) malformations like cerebellar hypoplasia (Abdel‐Salam et al, 2019; Nivelon et al, 1992) or holoprosencephaly (Pande et al, 2021), seizures (Abdel‐Salam et al, 2019), and ophthalmic abnormalities (Nivelon et al, 1992; Pande et al, 2021) were not seen in the present case. In contrast, this patient had simplified gyration which was not reported in previous individuals.…”

“…In contrast, this patient had simplified gyration which was not reported in previous individuals. Sex reversal and genital ambiguity has been reported in 46,XY individuals with biallelic HHAT variants (Mazen et al, 2022; Nivelon et al, 1992; Pande et al, 2021), while our patient and others with 46,XX karyotype have normal reproductive fitness. The clinical and other relevant findings of all patients with biallelic HHAT variants have been depicted in Table 1.…”

“…The second family with two affected siblings had a presentation of microcephaly, early infantile onset seizures, and cerebellar vermis hypoplasia (Abdel‐Salam et al, 2019). Third family comprised of two fetuses and one living proband in which severe microphthalmia, microcephaly, holoprosencephaly in one fetus, skeletal dysplasia, facial dysmorphism, and sex reversal were reported (Pande et al, 2021). Another recently reported patient presented with genital ambiguity and microcephaly with no other obvious abnormalities (Mazen et al, 2022).…”

Concepts in Multifactorial Etiology of Developmental Disorders: Gene-Gene and Gene-Environment Interactions in Holoprosencephaly

“…Autosomal recessive mutations in HPE have been documented, but are very rare. Examples include mutations in HHAT (encoding Hedgehog acyltransferase), PLCH1 (encoding phospholipase C eta-1), and STIL [encoding a factor required for maintenance of primary cilia, a subcellular structure critical for HH signaling ( Kakar et al, 2015 ; Mouden et al, 2015 ; Drissi et al, 2021 ; Pande et al, 2021 )].…”