A number sign (#) is used with this entry because of evidence that Muggenthaler-Chowdhury-Chioza syndrome (MCCS) is caused by homozygous or compound heterozygous mutation in the HYAL2 gene (603551) on chromosome 3p21.

Muggenthaler-Chowdhury-Chioza syndrome (MCCS) is an autosomal recessive disorder characterized by a recognizable pattern of craniofacial dysmorphism, most consistently hypertelorism and a broad flat nose, and myopia. Congenital cardiac anomalies are often present and may require early surgical intervention. Cleft lip and palate is common but not always observed (Fasham et al., 2022).

Shaheen et al. (2016) reported 2 affected individuals from a multiply consanguineous Saudi family (family 11) who had high myopia with facial dysmorphism and mutation in the HYAL2 gene. A clinical photograph of case 14DG1221 (IV:4) was published that showed hypertelorism, strabismus, broad nose, hypoplastic maxilla, micrognathia, and low-set ears. Her affected niece (case 15DG1187, V:2) also had cleft lip and palate. Muggenthaler et al. (2017) restudied this Saudi family as family 2 and noted additional features in the affected girls, including lens opacities, cupped ears, and bilateral single palmar creases. Echocardiography was performed in 1 patient (V:3) and showed an abnormal mitral valve with accessory tissue and a small restrictive perimembranous ventricular septal defect covered with tricuspid aneurysmal tissue; she also had mild conductive hearing loss. The other patient (VI:2) exhibited pectus excavatum.

Muggenthaler et al. (2017) reported 5 children from a large Amish pedigree (family 1) with craniofacial dysmorphism and myopia and mutation in the HYAL2 gene. All 5 patients had cleft lip and palate, which was unilateral in 1. Other craniofacial features included frontal bossing, hypertelorism, broad and flat nasal bridge and tip, cupped ears with thickened helices, and micrognathia. Four patients were myopic. Mild to moderate conductive hearing loss was present in 3 of the children, and 1 had severe sensorineural hearing loss. Congenital cardiac anomalies were noted in 3 patients, including 2 with dilated coronary sinus consistent with persistent left superior vena cava, and 1 with nonobstructive cor triatriatum sinister, a rare cardiac anomaly dividing the pulmonary venous confluence from the body of the left atrium with an anterior fenestration in the membrane. Other features included pectus excavatum in 3 of the 5 children and single palmar creases in 2.

Using GeneMatcher, Fasham et al. (2022) ascertained an additional 10 patients from 6 families of Amish, Romanian, Italian, and North European ancestry with frontonasal dysplasia and myopia and mutation in the HYAL2 gene, including 2 Ohio Amish sibs who were distant relatives of the Amish pedigree studied by Muggenthaler et al. (2017). Affected individuals shared distinctive craniofacial similarities, including frontal bossing, hypertelorism, broad and flat nasal tip, and cupped ears. Seven patients were myopic; vision status was unknown in the remaining 3 patients. Other common but variable clinical features included cleft lip and palate (unilateral and bilateral); congenital cardiac anomalies, including valvular and septal defects, coarctation of the aorta, tetralogy of Fallot, double-outlet right ventricle, and hypoplastic left heart; single palmar crease; and pectus excavatum.

The transmission pattern of MCCS in the Saudi family reported by Shaheen et al. (2016) and the Amish family studied by Muggenthaler et al. (2017) was consistent with autosomal recessive inheritance.

In a multiply consanguineous Saudi family (family 11) in which 2 members had frontonasal dysplasia and high myopia, Shaheen et al. (2016) performed autozygome analysis and identified a single autozygous interval on chromosome 3 (chr3: 40,899,164-54,379,802; GRCh37) that was exclusively shared by the 2 affected individuals.

By genomewide SNP analysis in a large Amish pedigree (family 1) in which 5 children had frontonasal dysplasia and myopia, Muggenthaler et al. (2017) identified a single notable shared autozygous region of 10.18 Mb at chromosome 3p21.31 (chr3: 46,310,893-56,499,374; GRCh38). Multipoint linkage analysis under the assumptions of autosomal recessive inheritance, full penetrance, and a disease allele frequency of 0.0001 yielded a lod score of 10.37 corresponding to the autozygous interval.

In a cohort of 33 consanguineous families with facial dysmorphism and/or skeletal dysplasia, Shaheen et al. (2016) performed autozygome analysis and whole-exome/genome sequencing and identified 2 affected members of a multiply consanguineous Saudi family (family 11) with facial dysmorphism and high myopia who were homozygous for a missense mutation in the HYAL2 gene (P250L; 603551.0001). Sanger sequencing validated the mutation and its segregation with disease in the family.

By whole-exome sequencing in an extended Amish pedigree (family 1) in which 5 children had craniofacial dysmorphism and myopia mapping to chromosome 3p21, Muggenthaler et al. (2017) identified homozygosity for a missense mutation in the HYAL2 gene (K148R; 603551.0002) that segregated with disease and was not found in public variant databases. However, it was identified in heterozygosity in 7 of 266 Amish controls, indicating an allele frequency of 0.013 in the Amish population. The authors noted that 1 of the 5 patients exhibited a rare cardiac anomaly, cor triatriatum sinister, and stated that this was the first molecular basis for that defect in humans.

In 10 patients from 6 families with frontonasal dysplasia and myopia, with or without congenital cardiac malformations and cleft lip/palate, Fasham et al. (2022) identified homozygosity or compound heterozygosity for mutations in the HYAL2 gene (see, e.g., 603551.0002-603551.0010). The mutations segregated with disease in the respective families, and were either not found or were rare in the gnomAD database. Functional analysis in transfected cells showed reduced or absent HYAL2 protein, and cell surface expression of the mutants was absent or present at low levels compared to wildtype HYAL2.

Chowdhury et al. (2013) found that Hyal2 -/- mice suffered from preweaning lethality, with only 9% of mice being Hyal2 -/- at weaning rather than the expected 25%. Of the viable Hyal2 -/- mice, 54% were smaller than littermates and exhibited rapid-onset lethargy, weight loss, dull coat, shortness of breath, and dilated left or right atrium, which the authors defined as the acute group. The remaining 46% developed slower onset of lethargy, loss of weight, and poor grooming, but not severe atrial dilation, which the authors defined as the nonacute group. About 43% of Hyal2 -/- mice were missing 1 kidney, but kidney loss was independent of atrial dilation and was not studied further. Both acute and nonacute groups displayed heart valve expansion, with accumulation of hyaluronan, altering the structure and organization of valves. The acute group had changes in heart structure in the upper ventricular region, close to the base of the heart. Both groups exhibited cardiac hypertrophy with an accumulation of extracellular matrix. Severe pulmonary fibrosis was observed in the acute group, but not in the nonacute group. Increased hyaluronan levels and size were seen in sera and hearts of both groups.

Muggenthaler et al. (2017) performed micro-CT studies of Hyal2 -/- mouse pups and observed an underdeveloped and underossified viscerocranium compared to littermate controls. Several central palate bones were underdeveloped, the vomer did not fuse centrally or form a head that articulated with the maxilla, and the ethmoid bone was nearly absent. Dissecting microscopy of the palates of Hyal2 -/- embryos from E18.5 to E19.5 revealed partial clefts and/or shortening of the secondary palate as well as abnormally formed rugae. Micro-CT confirmed reduced ossification and underdevelopment of the viscerocranial bones, particularly the vomer, consistent with submucosal cleft palate. The authors noted that this palatal malformation and clefting are likely to contribute significantly to the observed preweaning lethality in Hyal2-null mice. Histologic studies of P1 mice confirmed that the viscerocranial bones of all Hyal2 -/- mice were underdeveloped, and coronal sections showed the failed fusion between the epithelial surface of the vomeronasal organ and the dorsal side of the palate shelf. Hyaluronan levels were clearly increased in Hyal2-deficient tissues. The authors also noted that cor triatriatum sinister, a rare cardiac anomaly present in 1 of 7 human patients with HYAL2 mutations, had been detected in 50% of Hyal2 -/- mice.