Frank-ter Haar syndrome (FTHS) is an inherited disease associated with variants of the SH3PXD2B gene, encoding for the podosomal adaptor protein known as TKS4. FTHS is characterized by multiple skeletal abnormalities, developmental delay and severe craniofacial dysmorphology. This study provides an in-depth characterization of the calvarial phenotype of a mouse model of FTHS and investigates the potential underlying molecular and transcriptomic mechanisms. The Sh3Pxd2bnee-/- mouse presents with craniofacial malformations and disrupted suture patterning, as well as reduced osteoregeneration and decreased cell proliferation and migration observed both in vitro and in vivo, and impaired podosome formation. Transcriptomic analysis revealed downregulation of genes involved in ribosome biogenesis. Moreover, ribosomal RNA accumulates in cell protrusions of migrating cells. We established that the craniofacial phenotype of the Sh3Pxd2bnee-/- mouse is governed by impaired cell migration and proliferation due to dysfunctional podosome formation, particularly in neural crest-derived tissues. Transcriptomic and molecular data suggest altered ribosome-related processes, although further investigation is needed to clarify the underlying mechanisms.

Melnick-Needles syndrome (MNS) is a rare X-linked dominant skeletal dysplasia caused by pathogenic FLNA variants, primarily affecting females due to male lethality. Characterised by severe craniofacial and skeletal abnormalities, MNS exhibits marked phenotypic variability influenced by skewed X-inactivation, somatic mosaicism, and variant-specific functional consequences. Recent advances in next-generation sequencing and ACMG-based variant classification have refined diagnosis, particularly for pathogenic variants in exon 22, yet genotype-phenotype correlations remain incompletely defined. Differential diagnosis within the otopalatodigital spectrum, including OPD1, OPD2, and Frank-Ter Haar syndrome, remains challenging due to overlapping features, necessitating comprehensive radiological and molecular evaluation. Clinical manifestations span craniofacial dysmorphism, thoracic hypoplasia, respiratory compromise, and multisystem involvement. Management requires interdisciplinary coordination encompassing respiratory support, orthognathic surgery, dental reconstruction, and monitoring for complications such as glaucoma and psychiatric comorbidities. Evidence for the use of recombinant human bone morphogenetic protein-2 (rhBMP-2) and mandibular distraction techniques highlights surgical adaptability, though altered bone metabolism in MNS necessitates modified approaches. Rare associations with periventricular nodular heterotopia and bipolar disorder suggest a broader neurodevelopmental impact of FLNA dysfunction. Despite expanding clinical insight, the rarity of MNS limits population-level studies, constraining understanding of natural history and long-term outcomes. Future research must prioritise elucidating modifier genes, therapeutic targets such as antisense oligonucleotides, and prenatal detection strategies. A synthesis of genetic, clinical, and surgical domains is essential to optimise care pathways, improve prognosis, and inform genetic counselling for families affected by this phenotypically diverse and medically complex disorder.

Frank ter Haar syndrome (FTHS) is a rare and complex multisystem congenital genetic disorder that leads to craniofacial, cardiac, and skeletal abnormalities. We report the anesthesia and airway management of a child with FTHS who was referred for repair of atrial septal defect (ASD) and ventricular septal defect (VSD). The patient exhibited craniofacial and skeletal abnormalities, including craniosynostosis, micrognathia, a prominent forehead, hypertelorism, and anteverted nostrils. These features raised the possibility of a difficult airway. For patients with potential difficult airways undergoing elective surgery, the procedure should be postponed until all necessary equipment for managing a difficult airway is available.

Frank-Ter Haar syndrome (FTHS) is a rare genetic hereditary autosomal recessive disorder characterized by defective malformation of cardiovascular, craniofacial, and skeletal system. Mutations in the SH3PXD2B gene are a common cause in the development of FTHS. We recruited a family with two affected individuals (3-year-old female and 2-month-old male infant) having bilateral clubfoot. Family pedigree shows an autosomal recessive mode of inheritance. DNA was extracted from the blood samples of six members of the family. Whole exome sequencing was done for the two affected individuals and the variant was validated in the whole family by using Sanger sequencing approach. Whole exome sequencing (WES) data analysis identified a rare homozygous variant (c.280C>G; p.R94G) in the SH3PXD2B gene, and Sanger sequencing showed that the same variant perfectly segregates with the phenotype in the pedigree. Moreover, the variant is predicted to be damaging and deleterious by several computation tools. Revisiting the family members for detailed clinical analysis, we diagnosed the patients as having the typical phenotype of FTHS. This study enabled us to correctly diagnose the cases of FTHS in a family initially recruited for having bilateral clubfoot by using WES. Moreover, this study identified a novel homozygous missense variant (c.280C>G; p.R94G) in (NM_001308175.2) the SH3PXD2B gene as a causative variant for autosomal recessive FTHS. This finding supports the evidence that homozygous mutations in the SH3PXD2B gene are the main cause in the development of FTHS. Синдром Франка–Тер Хаара (Frank–Ter Haar syndrome, FTHS) – редкое генетическое заболевание с аутосомно-рецессивным типом наследования, характеризующееся аномалиями развития сердечно-сосудистой системы, костей лицевого черепа и скелета. Наиболее распространенной причиной развития данного синдрома являются мутации в гене SH3PXD2B. Для исследования была выбрана семья, в которой двое детей (трехлетняя девочка и двухмесячный мальчик) страдали двусторонней косолапостью. В семейной родословной указывался аутосомно-рецессивный тип наследования. Из крови шести членов семьи мы выделили образцы ДНК. Для упомянутых двоих детей было проведено полное секвенирование экзома, а секвенированием по Сэнгеру подтверждено наличие мутантного варианта у всех членов семьи. По результатам анализа данных полноэкзомного секвенирования (WES) была выявлена редкая гомозиготная мутация (c.280C>G; p.R94G) в гене SH3PXD2B. Секвенирование по Сэнгеру показало, что эта мутация идеально сегрегирует с указанным фенотипом в родословной. Более того, при использовании ряда инструментальных средств получены данные, предсказывающие вредность и опасность этой мутации. При повторном посещении членов семьи с целью проведения развернутого клинического анализа было установлено, что фенотип двоих детей, страдавших двусторонней косолапостью, характерен для больных с синдромом FTHS. Таким образом, исследование позволило безошибочно диагностировать синдром FTHS в семье, первоначально выбранной в связи с двусторонней косолапостью у ее членов, с помощью WES. Более того, наше исследование показало, что причиной развития синдрома FTHS с аутосомно-рецессивным типом наследования была вновь выявленная гомозиготная миссенсмутация (c.280C>G; p.R94G) в гене (NM_001308175.2) SH3PXD2B. Это служит дополнительным подтверждением существующих данных о том, что гомозиготные мутации в гене SH3PXD2B являются основной причиной развития синдрома FTHS.

Ventricular septal defects (VSDs) are recognized as one of the commonest congenital heart diseases (CHD), accounting for up to 40% of all cardiac malformations, and occur as isolated CHDs as well as together with other cardiac and extracardiac congenital malformations in individual patients and families. The genetic etiology of VSD is complex and extraordinarily heterogeneous. Chromosomal abnormalities such as aneuploidy and structural variations as well as rare point mutations in various genes have been reported to be associated with this cardiac defect. This includes both well-defined syndromes with known genetic cause (e.g., DiGeorge syndrome and Holt-Oram syndrome) and so far undefined syndromic forms characterized by unspecific symptoms. Mutations in genes encoding cardiac transcription factors (e.g., NKX2-5 and GATA4) and signaling molecules (e.g., CFC1) have been most frequently found in VSD cases. Moreover, new high-resolution methods such as comparative genomic hybridization enabled the discovery of a high number of different copy number variations, leading to gain or loss of chromosomal regions often containing multiple genes, in patients with VSD. In this chapter, we will describe the broad genetic heterogeneity observed in VSD patients considering recent advances in this field.