Clinical spectrum of females with HCCS mutation: from no clinical signs to a neonatal lethal form of the microphthalmia with linear skin defects (MLS) syndrome

Abstract

BackgroundSegmental Xp22.2 monosomy or a heterozygous HCCS mutation is associated with the microphthalmia with linear skin defects (MLS) or MIDAS (microphthalmia, dermal aplasia, and sclerocornea) syndrome, an X-linked disorder with male lethality. HCCS encodes the holocytochrome c-type synthase involved in mitochondrial oxidative phosphorylation (OXPHOS) and programmed cell death.MethodsWe characterized the X-chromosomal abnormality encompassing HCCS or an intragenic mutation in this gene in six new female patients with an MLS phenotype by cytogenetic analysis, fluorescence in situ hybridization, sequencing, and quantitative real-time PCR. The X chromosome inactivation (XCI) pattern was determined and clinical data of the patients were reviewed.ResultsTwo terminal Xp deletions of ≥11.2 Mb, two submicroscopic copy number losses, one of ~850 kb and one of ≥3 Mb, all covering HCCS, 1 nonsense, and one mosaic 2-bp deletion in HCCS are reported. All females had a completely (>98:2) or slightly skewed (82:18) XCI pattern. The most consistent clinical features were microphthalmia/anophthalmia and sclerocornea/corneal opacity in all patients and congenital linear skin defects in 4/6. Additional manifestations included various ocular anomalies, cardiac defects, brain imaging abnormalities, microcephaly, postnatal growth retardation, and facial dysmorphism. However, no obvious clinical sign was observed in three female carriers who were relatives of one patient.ConclusionOur findings showed a wide phenotypic spectrum ranging from asymptomatic females with an HCCS mutation to patients with a neonatal lethal MLS form. Somatic mosaicism and the different ability of embryonic cells to cope with an OXPHOS defect and/or enhanced cell death upon HCCS deficiency likely underlie the great variability in phenotypes.

Histiocytoid cardiomyopathy and microphthalmia with linear skin defects syndrome: phenotypes linked by truncating variants in NDUFB11

“…Wimplinger et al 2006 reported a female, born to healthy nonconsanguineous parents after an uneventful pregnancy, found to have bilateral microphthalmia and sclerocornea but no erythematous skin lesions. She had a de novo HCCS nonsense variant (c.589C > T; p.(R197*)) that was also reported in an additional case with both MLS and histiocytoid CM (van Rahden et al 2014). Around 1 yr of age she was reported to have developed “idiopathic VT” (Wimplinger et al 2006).…”

“…We hypothesize that HCCS (OMIM 30056) and COX7B (OMIM 300885) , which are X-linked genes encoding or targeting mitochondrial proteins and are implicated in MLS, are good candidate genes for histiocytoid CM. We note that van Rahden et al (2014) have reported previously a female child with a de novo HCCS nonsense variant (c.589C > T; p.(R197*)) and extremely skewed X-inactivation (98:2) with classical features of MLS including linear skin defects on her neck, microphthalmia, anophthalmia, and sclerocornea, who died at 4 mo with ventricular tachycardia (VT) and was found to have histiocytoid CM on postmortem examination, further supporting that MLS and histiocytoid CM are allelic disorders. However, no rare variants were found in HCCS or COX7B in seven additional histiocytoid CM cases without NDUFB11 variants (four described here, three in Shehata et al 2015), though this small series does not exclude a role in “isolated” histiocytoid CM.…”

“…Other causes of phenotypic variability could include copy-number variation or common or rare modifier variants contributing to mitochondrial function (Shehata et al 2015). Furthermore, phenotypic variability may reflect differing abilities of developing tissues and organs in embryonic cells to handle a defective MRC system (van Rahden et al 2014). …”

Linear skin defects and microphthalmia

“…The diagnosis is supported by minor criteria (Table ) and/or a family history consistent with X‐linked inheritance with male lethality. It has been hypothesized that the particular involvement of neural crest cells explains the linear skin defects restricted to the face and neck . The defects demonstrate dermoscopic features of telangiectasias and absence of sebaceous glands and vellus hair .…”

Microphthalmia with linear skin defects (MLS) syndrome: familial presentation

“…MLS syndrome is genetically heterogenous, with heterozygous mutations in the gene for human holocytochrome c synthase ( HCCS ) having been identified in MLS‐affected females . In total, 62 cases of MLS syndrome have been reported, of which 11 cases were familial . We present a further case of familial MLS.…”