Happle-Tinschert syndrome variable phenotype as part of the mosaic hedgehog spectrum: Report of three cases.

Happle-Tinschert syndrome is a rare genodermatosis caused by a postzygotic mutation in SMO gene. The most recognized clinical findings include segmentally arranged basaloid follicular hamartomas, nevoid hypertrichosis, linear atrophoderma, and hypopigmentation or hyperpigmentation following Blaschko lines associated with osseous, dental, and cerebral alterations. We report three additional cases, two of which lacked the pathognomonic basaloid follicular hamartomas, with genetic confirmation and detailed clinical characterization and describe new cutaneous features of this infrequent syndrome.

Intrafamilial phenotypic variability in autosomal recessive DOCK6-related Adams-Oliver syndrome.

Adams-Oliver syndrome (AOS) is diagnosed in presence of aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). The autosomal recessive (AR) DOCK6-related form of AOS is most often associated with a severe phenotype including also central nervous system and ocular abnormalities. We report a sister and brother with different expression of the phenotype. Both were compound heterozygous pathogenic variants in the DOCK6 gene, including a heterozygous c.5939+2T > C intronic variant that was maternally inherited, and a heterozygous deletion of exons 10 to 21 that was paternally inherited. The sister had microcephaly, periventricular calcifications, minor retinal vasculopathy, and mild impaired neurodevelopment, but only very subtle limb abnormalities and no ACC. Her brother showed a classical DOCK6-related AOS phenotype, including a severe bilateral peripheral ischemic retinopathy. From a review of 22 molecularly confirmed cases with DOCK6-related AOS with ophthalmic examination, we found that 16 of them had retinal vascular pathology (72.7%), confirming as the major ocular anomaly. Documented intrafamilial variability in our family and the evidence revised from previous reports, confirm that AR DOCK6-related AOS expressivity can produce a "milder" phenotype without ACC or TTLD, which could be underdiagnosed in simplex cases because it is difficult to recognize out of a familial context. Therefore, in order to know its real magnitude is required the future inclusion of DOCK6 gene in NGS panels directed to the study of simplex cases of patients with microcephaly, periventricular calcifications, retinal vasculopathy, and/or cardiovascular defects.

Outcomes in growth hormone-treated Noonan syndrome children: impact of PTPN11 mutation status.

Introduction: Mutations in PTPN11 are associated with Noonan syndrome (NS). Although the effectiveness of growth hormone therapy (GHT) in treating short stature due to NS has been previously demonstrated, the effect of PTPN11 mutation status on the long-term outcomes of GHT remains to be elucidated. Methods: This analysis included pooled data from the observational American Norditropin Studies: Web-Enabled Research Program (NCT01009905) and the randomized, double-blinded GHLIQUID-4020 clinical trial (NCT01927861). Pediatric patients with clinically diagnosed NS and confirmed PTPN11mutation status were eligible for inclusion. The effectiveness analysis included patients who were GHT-naïve and pre-pubertal at GHT start. Growth outcomes and safety were assessed over 4 years of GHT (Norditropin®, Novo Nordisk A/S). Results: A total of 69 patients were included in the effectiveness analysis (71% PTPN11 positive). The proportion of females was 32.7 and 30.0% in PTPN11-positive and negative patients, respectively, and mean age at GHT start was 6.4 years in both groups. Using general population reference data, after 4 years of GHT, the mean (s.d.) height SD score (HSDS) was -1.9 (1.1) and -1.7 (0.8) for PTPN11-positive and PTPN11-negative patients, respectively, with no statistical difference observed between groups. The mean (s.d.) change in HSDS at 4 years was +1.3 (0.8) in PTPN11-positive patients and +1.5 (0.7) in PTPN11-negative patients (no significant differences between groups). Safety findings were consistent with previous analyses. Conclusions: GHT resulted in improved growth outcomes over 4 years in GHT-naïve, pre-pubertal NS patients, irrespective of PTPN11 mutation status.

Expansion of the phenotypic spectrum and description of molecular findings in a cohort of patients with oculocutaneous mosaic RASopathies.

BACKGROUND: Postzygotic KRAS, HRAS, NRAS, and FGFR1 mutations result in a group of mosaic RASopathies characterized by related developmental anomalies in eye, skin, heart, and brain. These oculocutaneous disorders include oculoectodermal syndrome (OES) encephalo-cranio-cutaneous lipomatosis (ECCL), and Schimmelpenning-Feuerstein-Mims syndrome (SFMS). Here, we report the results of the clinical and molecular characterization of a novel cohort of patients with oculocutaneous mosaic RASopathies. METHODS: Two OES, two ECCL, and two SFMS patients were ascertained in the study. In addition, two subjects with unilateral isolated epibulbar dermoids were also enrolled. Molecular analysis included PCR amplification and Sanger sequencing of KRAS, HRAS, NRAS, and FGFR1 genes in DNA obtained from biopsies (skin/epibulbar dermoids), buccal mucosa, and blood leukocytes. Massive parallel sequencing was employed in two cases with low-level mosaicism. RESULTS: In DNA from biopsies, mosaicism for pathogenic variants, including KRAS p.Ala146Thr in two OES subjects, FGFR1 p.Asn546Lys and KRAS p.Ala146Val in ECCL patients, and KRAS p.Gly12Asp in both SFMS patients, was demonstrated. No mutations were shown in DNA from conjunctival lesions in two subjects with isolated epibubar dermoids. CONCLUSION: Our study allowed the expansion of the clinical spectrum of mosaic RASopathies and supports that mosaicism for recurrent mutations in KRAS and FGFR1 is a commonly involved mechanism in these rare oculocutaneous anomalies.

Novel FREM1 mutations in a patient with MOTA syndrome: Clinical findings, mutation update and review of FREM1-related disorders literature.

Manitoba-oculo-tricho-anal (MOTA) syndrome is an uncommon condition arising from biallelic mutations of FREM1 gene and clinically characterized by a variable spectrum of eyelid malformations, aberrant hairline, bifid or broad nasal tip, and gastrointestinal anomalies. In this report, we describe a patient with a phenotype compatible with MOTA syndrome (aberrant anterior hair line, hypertelorism, unilateral anophthalmia, and bifid and broad nasal tip) in whom two novel FREM1 mutations (c.305 A > G, p.Asp102Gly; and c.2626delG, p.Val876Tyrfs*16) were identified in the compound heterozygous state, thus broadening the mutational spectrum of the disease. We performed a literature review of the clinical and genetic features of individuals carrying FREM1 mutations.

Health and quality of life in adults with Noonan syndrome.

OBJECTIVE: To obtain information on health and quality of life in adults with Noonan syndrome. STUDY DESIGN: From a cohort of 144 children with the diagnosis of Noonan syndrome whose height data had been published 23 years ago, 103 pediatric files providing adequate data were identified. Participants were sent questionnaires and asked to provide saliva for DNA analysis and to return for physical examination. RESULTS: Ten of 103 individuals had died, 3 of them suddenly (standardized mortality ratio, 3.00; 95% CI, 1.44-5.52). Eighty-one individuals could be contacted by mail, with a positive response from 45. Genotyping in 36 of 45 participants revealed characteristic mutations in 61%. Median age at follow-up was 42.8 years. Mean adult heights were 169.2 cm (men) and 154.4 cm (women). In comparison with the general population, participants had lower educational status and lived more frequently without any partner. According to the response to the Short Form-36 questionnaire, quality of life was not impaired. CONCLUSIONS: Individuals with Noonan syndrome have higher mortality, lower education, and rarely partnership. Quality of life according to self-reported Short Form-36 was good. Men grew taller than previously reported from this cohort.

Fraser and Ablepharon macrostomia phenotypes: concurrence in one family and association with mutated FRAS1.

To date, Fraser syndrome (FS) and Ablepharon macrostomia syndrome (AMS) have been considered distinct disorders, but they share strikingly similar patterns of congenital abnormalities, specifically craniofacial anomalies. While recent research has led to the identification of the genes FRAS1 and FREM2 as the cause of FS, the genetic basis of AMS continues to be enigmatic. We report on the concurrence of AMS-like and Fraser phenotypes in a Brazilian family. Both affected sibs were homozygous for a novel splice site mutation in the FRAS1 gene. Extensive studies on mRNA expression indicated that this mutation most likely leads to loss of function as most previously reported FRAS1 mutations associated with FS. We conclude that a phenotype resembling AMS is a rare clinical expression of FS with no obvious genotype-phenotype correlation. However, the molecular basis of "true" AMS which has been reported as a sporadic disorder in all cases but one, and so far with no relation to FS, is probably different and still needs to be further investigated.

Genotype-phenotype correlations in Noonan syndrome.

OBJECTIVE: To study genotype-phenotype correlations in a cohort of clinically well-characterized pediatric patients with Noonan syndrome (NS). Study design Fifty-seven unrelated patients with the clinical diagnosis of NS ascertained according to standardized inclusion criteria were prospectively enrolled. Mutational analysis was performed by direct sequencing of the entire coding sequence of the PTPN11 gene. RESULTS: Sixteen known and 3 novel PTPN11 mutations could be detected in 60% of index patients, in all familial and in 52% of the sporadic cases. Presence of pulmonic stenosis, short stature, easy bruising, and thorax deformities was significantly associated with a PTPN11 mutation, whereas cardiomyopathy was more common in patients without a mutation. On average, PTPN11 mutation-negative probands fulfilled fewer clinical criteria of NS, but more than half-among them all with cardiomyopathy-had the full clinical picture of NS indistinguishable from typical cases with PTPN11 mutation. CONCLUSIONS: The phenotype of NS due to PTPN11 mutations is clinically unambiguous in the majority of patients and represents a highly penetrant trait. Individuals with the clinical diagnosis of NS but without a PTPN11 mutation presumably represent a heterogeneous group in which patients with cardiomyopathy appear to constitute an interesting subgroup for future research.

Treatment of two patients with Herlitz junctional epidermolysis bullosa with artificial skin bioequivalents.

OBJECTIVE: To evaluate the effects of a treatment with artificial skin bioequivalents in Herlitz junctional epidermolysis bullosa (H-JEB). METHODS: Two infants, both homozygous for the Herlitz mutation R635X in the LAMB3 gene, who had refractory anemia and hypoproteinemia as a result of a continuous loss of body fluids through multiple large erosions, were treated with artificial skin bioequivalents. RESULTS: In the first patient, 10 of 13 acute or chronic wounds were found healed 3 to 6 weeks after the treatment, and the protein, iron, and hemoglobin levels normalized. Normal weight gain and marked improvement of the quality of life for this patient's family have been evident since. Nine treated wounds remained healed for at least 18 weeks and appeared to be more resistant to trauma. In a skin biopsy from a treated site obtained after 9 weeks, DNA of the graft was still detectable by polymerase chain reaction. In the second patient, who was treated at a late stage of the disease, only 2 of 18 chronic wounds were found healed at 3 weeks after the treatment. One site remained healed completely, and some additional islets of the grafts persisted for longer. There were no adverse events. CONCLUSION: Early treatment with artificial skin substitutes may improve the clinical course of H-JEB. However, a true cure of the cutaneous manifestations of H-JEB would require gene therapy of autologous epidermal stem cells, which could then be transplanted by using this or a similar cultured skin bioequivalent.