A European guideline on Robin Sequence was developed within the European Reference Network for rare and/or complex craniofacial anomalies and ear, nose, and throat disorders. The guideline provides an overview of optimal care provisions for patients with Robin Sequence and recommendations for the improvement of care.

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Mandibuloacral Dysplasia with type B lipodystrophy (MADB) is a rare premature aging disorder with an autosomal recessive inheritance pattern. MADB is characterized by brittle hair, mottled, atrophic skin, generalized lipodystrophy, insulin resistance, metabolic complications and skeletal features like stunted growth, mandibular and clavicular hypoplasia and acro-osteolysis of the distal phalanges. MADB is caused by reduced activity of the enzyme zinc metalloprotease ZMPSTE24 resulting from compound heterozygous or homozygous mutations in ZMPSTE24.
In 2012, and again in 2018, eight related patients from the remote tropical rainforest of inland Suriname were analysed for dysmorphic features. DNA analysis was performed and clinical features were documented. We also analysed all previously reported genetically confirmed MADB patients from literature (n = 12) for their clinical features. Based on the features of all cases (n = 20) we defined major criteria as those present in 85-100% of all MADB patients and minor criteria as those present in 70-84% of patients.
All the Surinamese patients are of African descent and share the same homozygous c.1196A > G, p.(Tyr399Cys) missense variant in the ZMPSTE24 gene, confirming MADB. Major criteria were found to be: short stature, clavicular hypoplasia, delayed closure of cranial sutures, high palate, mandibular hypoplasia, dental crowding, acro-osteolysis of the distal phalanges, hypoplastic nails, brittle and/or sparse hair, mottled pigmentation, atrophic and sclerodermic skin, and calcified skin nodules. Minor criteria were (generalized or partial) lipoatrophy of the extremities, joint contractures and shortened phalanges. Based on our detailed clinical observations, and a review of previously described cases, we propose that the clinical diagnosis of MADB is highly likely if a patient exhibits ≥4 major clinical criteria OR ≥ 3 major clinical criteria and ≥ 2 minor clinical criteria.
We report on eight related Surinamese patients with MADB due to a homozygous founder mutation in ZMPSTE24. In low-income countries laboratory facilities for molecular genetic testing are scarce or lacking. However, because diagnosing MADB is essential for guiding clinical management and for family counselling, we defined clinical diagnostic criteria and suggest management guidelines.

Pediatric obstructive sleep apnea, characterized by partial or complete obstruction of the upper airway during sleep, is associated with multiple adverse neurodevelopmental and cardiometabolic consequences. It is common in healthy children and occurs with a higher incidence among infants and children with craniofacial anomalies. Although soft-tissue hypertrophy is the most common cause, interplay between soft tissue and bone structure in children with craniofacial differences may also contribute to upper airway obstruction. Snoring and work of breathing are poor predictors of obstructive sleep apnea, and the gold standard for diagnosis is overnight polysomnography. Most healthy children respond favorably to adenotonsillectomy as first-line treatment, but 20 percent of children have obstructive sleep apnea refractory to adenotonsillectomy and may benefit from positive airway pressure, medical therapy, orthodontics, craniofacial surgery, or combined interventions. For children with impairment of facial skeletal growth or craniofacial anomalies, rapid maxillary expansion, midface distraction, and mandibular distraction have all been demonstrated to have therapeutic value and may significantly improve a child\'s respiratory status. This Special Topic article reviews current theories regarding the underlying pathophysiology of pediatric sleep apnea, summarizes standards for diagnosis and management, and discusses treatments in need of further investigation, including orthodontic and craniofacial interventions. To provide an overview of the spectrum of disease and treatment options available, a deliberately broad approach is taken that incorporates data for both healthy children and children with craniofacial anomalies.

In recent years there has been a few numbers of studies on psychosocial aspects of patients with craniofacial anomalies in the world. Current research surrounding psychological aspects of craniofacial anomalies suffers from various inconsistencies as reported by the results which may be due to differences in methodology that has made interpretation of findings very difficult. This article aims to present an evaluation of methodological errors and inconsistent findings in such studies. A thorough search based on electronic data base was done utilizing the following words: \"craniofacial anomalies\", \"psychosocial impact\". The resultant studies were evaluated based on the methodology and various lacunae, pitfalls were summed up. The results indicated that most of the studies suffer from various methodological errors. Several guidelines were fabricated so as to minimize error and maximize accuracy. The authors recommend these guidelines for future research design of studies related to psychosocial aspects of patients with craniofacial anomalies.

The deletion 9p syndrome is caused by a constitutional monosomy of part of the short arm of chromosome 9. It is clinically characterized by dysmorphic facial features (trigonocephaly, midface hypoplasia, and long philtrum), hypotonia and mental retardation. Deletion 9p is known to be heterogeneous and exhibits variable deletion sizes. The critical region for a consensus phenotype has been reported to be located within a approximately 4-6 Mb interval on 9p22. In the present study, deletion breakpoints were determined in 13 Dutch patients by applying fluorescence in situ hybridization (FISH) and in some specific cases by array-based comparative genomic hybridization (array CGH). No clear genotype-phenotype correlation could be established for various developmental features. However, we were able to narrow down the critical region for deletion 9p syndrome to approximately 300 kb. A functional candidate gene for trigonocephaly, the CER1 gene, appeared to be located just outside this region. Sequence analysis of this gene in nine additional patients with isolated trigonocephaly did not reveal any pathogenic mutations.

In order to contribute to clinical delineation of midline facial defects with hypertelorism (MFDH) and to etiologic diagnosis of the isolated form, 31 patients with MFDH unaffected by known syndromic associations were evaluated. Group A included patients personally examined by the authors, while Group B included those previously evaluated by other geneticists. Among the 14 patients from Group A, there were 7 with distinct pictures of multiple congenital anomalies. In Group B, 5 of the 17 patients also exhibited a distinct pattern of defects. Among isolated MFDH, there was association with anomalies of the skull and facial bones (13/14), otorhinologic (11/16), central nervous system (9/16), and ocular (6/7), and audiologic (3/16); 1/3 of the cases had a relevant gestational intercurrences. Isolated FNM may have involvement of environmental components in some cases; the possibility of a syndromic picture should be extensive investigated. Follow-up of such patients must include the examinations herein performed.

The Kabuki syndrome, or Niikawa-Kuroki syndrome, is a clinically recognizable syndrome of unknown etiology. Clinical findings include early hypotonia, joint laxity, developmental delay, facial dysmorphism, persistent fetal fingertip pads, cleft palate, hypodontia, lip nodules, heart defects, and a variety of other structural defects. Behavior in general is social and pleasant. In collaboration with the Dutch Kabuki Network, we evaluated the medical data of 20 individuals diagnosed with the syndrome and compared them with data from the literature. In our literature review we used convincing cases only. Frequent findings in the oral region are under-reported in the literature: apart from the cleft palate (in about 50%), hypodontia with predominantly absence of the upper lateral incisors, and a full lower lip with symmetrical nodules, or (in a minority) lip-pits are frequent findings. Also under-reported is the presence of a thickened nuchal fold during pregnancy and hydrops in the neonatal period. Clinical recognition in the neonate is difficult. Towards early puberty acute and serious weight excess has been experienced. We suggest that a cytogenetic abnormality should be ruled out in all cases. We provide further guidelines for preventive management.

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