RESUMEN
Holoprosencephaly is an anomaly in the division of the prosencephalon into cerebral hemispheres during the second month of gestation. Patients can present with early-onset obesity favoured by the cognitive impairment. We present a case of a 24 year-old woman with holoprosencephaly and class III obesity who was treated by 2.4 mg/week SEMAGLUTIDE. Her body weight decreased from 115.3 to 94.3 kg after one-year (18% of total body weight loss). In addition, she presented a marked reduction in self- and hetero-aggressive behaviour when exposed to the sight of food. The treatment was well tolerated, with the exception of a few vomiting when eating palatable food too quickly. GLP1-RAs may be interesting for obesity treatment in the context of neurodevelopmental disorders. They appear to reduce compulsive eating and aggressive behaviour, particularly in relation to exposure to food, and lead to weight loss similar to that seen in people without neurodevelopmental disorders.
Asunto(s)
Receptor del Péptido 1 Similar al Glucagón , Holoprosencefalia , Trastornos del Neurodesarrollo , Obesidad , Humanos , Femenino , Holoprosencefalia/complicaciones , Receptor del Péptido 1 Similar al Glucagón/agonistas , Adulto Joven , Obesidad/complicaciones , Trastornos del Neurodesarrollo/etiología , Péptidos Similares al Glucagón/análogos & derivados , Péptidos Similares al Glucagón/uso terapéutico , Pérdida de PesoRESUMEN
Sonic hedgehog signaling molecule (SHH) is a key molecule in the cilia-mediated signaling pathway and a critical morphogen in embryogenesis. The association between loss-of-function variants of SHH and holoprosencephaly is well established. In mice experiments, reduced or increased signaling of SHH have been shown to be associated with narrowing or excessive expansion of the facial midline, respectively. Herein, we report two unrelated patients with de novo truncating variants of SHH presenting with hypertelorism rather than hypotelorism. The first patient was a 13-year-old girl. Her facial features included hypertelorism, strabismus, telecanthus, malocclusion, frontal bossing, and wide widow's peak. She had borderline developmental delay and agenesis of the corpus callosum. She had a nonsense variant of SHH: Chr7(GRCh38):g.155802987C > T, NM_000193.4:c.1302G > A, p.(Trp434*). The second patient was a 25-year-old girl. Her facial features included hypertelorism and wide widow's peak. She had developmental delay and agenesis of the corpus callosum. She had a frameshift variant of SHH: Chr7(GRCh38):g.155803072_155803074delCGGinsT, NM_000193.4:c.1215_1217delCCGinsA, p.(Asp405Glufs*92). The hypertelorism phenotype contrasts sharply with the prototypical hypotelorism-holoprosencephaly phenotype associated with loss-of-function of SHH. We concluded that a subset of truncating variants of SHH could be associated with hypertelorism rather than hypotelorism.
Asunto(s)
Proteínas Hedgehog , Holoprosencefalia , Hipertelorismo , Fenotipo , Humanos , Proteínas Hedgehog/genética , Femenino , Holoprosencefalia/genética , Holoprosencefalia/patología , Adolescente , Hipertelorismo/genética , Hipertelorismo/patología , Adulto , Mutación/genéticaRESUMEN
OBJECTIVE: Holoprosencephaly (HPE) is the most common aberration of forebrain development, and it leads to a wide spectrum of developmental and craniofacial anomalies. HPE etiology is highly heterogeneous and includes both chromosomal abnormalities and single-gene defects. METHODS: Here, we report an FGFR1 heterozygous variant detected by prenatal exome sequencing and inherited from the asymptomatic mother, in association with recurrent neurological abnormalities in the HPE spectrum in two consecutive pregnancies. RESULTS: Individuals with germline pathogenic variants in FGFR1 (MIM: 136350) show extensive phenotypic variability, which ranges from asymptomatic carriers to hypogonadotropic hypogonadism, arhinencephaly, Kallmann's syndrome with associated features such as cleft lip and palate, skeletal anomalies, isolated HPE, and Hartsfield syndrome. CONCLUSION: The presented case supports the role of exome sequencing in prenatal diagnosis when fetal midline structural anomalies are suggestive of a genetic etiology, as early as the first trimester of gestation. The profound heterogeneity of FGFR1 allelic disorders needs to be considered when planning prenatal screening even in asymptomatic carriers.
Asunto(s)
Holoprosencefalia , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos , Humanos , Femenino , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Embarazo , Holoprosencefalia/genética , Holoprosencefalia/diagnóstico , Adulto , Diagnóstico Prenatal/métodos , Secuenciación del Exoma , Ultrasonografía Prenatal , Prosencéfalo/anomalías , Prosencéfalo/embriología , HeterocigotoRESUMEN
OBJECTIVES: The main objective of this study was to evaluate how an apparently minor anomaly of the sphenoid bone, observed in a haploinsufficient mouse model for Sonic Hedgehog (Shh), affects the growth of the adult craniofacial region. This study aims to provide valuable information to orthodontists when making decisions regarding individuals carrying SHH mutation. MATERIALS AND METHODS: The skulls of embryonic, juvenile and adult mice of two genotypes (Shh heterozygous and wild type) were examined and measured using landmark-based linear dimensions. Additionally, we analysed the clinical characteristics of a group of patients and their relatives with SHH gene mutations. RESULTS: In the viable Shh+/ - mouse model, bred on a C57BL/6J background, we noted the presence of a persistent foramen at the midline of the basisphenoid bone. This particular anomaly was attributed to the existence of an ectopic pituitary gland. We discovered that this anomaly led to premature closure of the intrasphenoidal synchondrosis and contributed to craniofacial deformities in adult mice, including a longitudinally shortened skull base. This developmental anomaly is reminiscent of that commonly observed in human holoprosencephaly, a disorder resulting from a deficiency in SHH activity. However, sphenoid morphogenesis is not currently monitored in individuals carrying SHH mutations. CONCLUSION: Haploinsufficiency of Shh leads to isolated craniofacial skeletal hypoplasia in adult mouse. This finding highlights the importance of radiographic monitoring of the skull base in all individuals with SHH gene mutations.
Asunto(s)
Proteínas Hedgehog , Holoprosencefalia , Adulto , Animales , Humanos , Ratones , Proteínas Hedgehog/genética , Holoprosencefalia/genética , Ratones Endogámicos C57BL , Mutación , Hueso EsfenoidesRESUMEN
BACKGROUND: Abortion and fetal death are common in fetuses with holoprosencephaly, so genetic examinations often have to be made in a post-mortem setting. The efficiency of the conventional karyotyping using cultured fibroblasts in these situations is limited due to frequent culture failure. In the current study, archived cases of holoprosencephaly, where post-mortem genetic evaluation was requested and sufficient frozen material was available, were reevaluated using the quantitative fluorescence polymerase chain reaction (QF-PCR) technique. METHODS: Testing for aneuploidies of chromosomes 13, 15, 16, 18, 21, 22, X, and Y with the QF-PCR technique was carried out on DNA isolated from archived frozen chorionic villi in seven cases of holoprosencephaly. RESULTS: QF-PCR was successful in all seven cases. Two cases of trisomy 13, two cases of triploidy, and one case of trisomy 18 was found meaning a 71% diagnostic yield. The success rate of QF-PCR (100%, 7/7) was superior compared to conventional karyotyping (43%, 3/7). CONCLUSIONS: Rapid aneuploidy testing using the QF-PCR technique is a simple, reliable, time- and cost-effective method sufficient to conclude the etiologic investigation in the majority of holoprosencephaly cases post-mortem.
Asunto(s)
Holoprosencefalia , Embarazo , Femenino , Humanos , Diagnóstico Prenatal/métodos , Aneuploidia , Reacción en Cadena de la Polimerasa/métodos , CariotipificaciónRESUMEN
PURPOSE: DISP1 encodes a transmembrane protein that regulates the secretion of the morphogen, Sonic hedgehog, a deficiency of which is a major cause of holoprosencephaly (HPE). This disorder covers a spectrum of brain and midline craniofacial malformations. The objective of the present study was to better delineate the clinical phenotypes associated with division transporter dispatched-1 (DISP1) variants. METHODS: This study was based on the identification of at least 1 pathogenic variant of the DISP1 gene in individuals for whom detailed clinical data were available. RESULTS: A total of 23 DISP1 variants were identified in heterozygous, compound heterozygous or homozygous states in 25 individuals with midline craniofacial defects. Most cases were minor forms of HPE, with craniofacial features such as orofacial cleft, solitary median maxillary central incisor, and congenital nasal pyriform aperture stenosis. These individuals had either monoallelic loss-of-function variants or biallelic missense variants in DISP1. In individuals with severe HPE, the DISP1 variants were commonly found associated with a variant in another HPE-linked gene (ie, oligogenic inheritance). CONCLUSION: The genetic findings we have acquired demonstrate a significant involvement of DISP1 variants in the phenotypic spectrum of midline defects. This underlines its importance as a crucial element in the efficient secretion of Sonic hedgehog. We also demonstrated that the very rare solitary median maxillary central incisor and congenital nasal pyriform aperture stenosis combination is part of the DISP1-related phenotype. The present study highlights the clinical risks to be flagged up during genetic counseling after the discovery of a pathogenic DISP1 variant.
Asunto(s)
Alelos , Holoprosencefalia , Fenotipo , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Anodoncia , Labio Leporino/genética , Labio Leporino/patología , Fisura del Paladar/genética , Fisura del Paladar/patología , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/patología , Heterocigoto , Holoprosencefalia/genética , Holoprosencefalia/patología , Homocigoto , Incisivo/anomalías , Proteínas de la Membrana/genética , Mutación Missense/genéticaAsunto(s)
Dedos/anomalías , Holoprosencefalia , Polidactilia , Dedos del Pie/anomalías , Embarazo , Femenino , Humanos , Holoprosencefalia/diagnóstico por imagen , Holoprosencefalia/genética , Primer Trimestre del Embarazo , Síndrome de la Trisomía 13/diagnóstico , Polidactilia/diagnóstico , Polidactilia/genética , Trisomía/diagnóstico , Trisomía/genética , Ultrasonografía PrenatalRESUMEN
BACKGROUND: Holoprosencephaly is a rare (1/16,000 livebirths) and severe brain malformation occurring during early embryogenesis. The malformation originates from absent or incomplete forebrain division and is associated with altered embryonic patterning. OBJECTIVES: A narrative review to identify and assess the evidence on non-genetic risk factors. RESULTS: Genes involved include sonic hedgehog, Zinc finger protein, SIX homeobox 3. Pregestational diabetes, with periconceptional hyperglycaemia, is the main non-genetic risk factor; increased oxidative stress in neuroectoderm, in particular neural crest cells, appears as the main mechanism. Several widespread pollutants, including inorganic arsenic, PFAS and PCBs, may increase the risk of pregestational diabetes by altering metabolic factors, including lipids and insulin. A scenario "widespread exposures-rare outcomes in susceptible subjects" suggests that exposure to dietary pollutants may increase the risk of pregestational diabetes, hence of holoprosencephaly in susceptible embryos. CONCLUSIONS: This complex pathway is plausible and worth being investigated; moreover, it highlights the importance of assessing risk factors, and the associated uncertainties, in order to support primary prevention strategies for multifactorial malformations.
Asunto(s)
Diabetes Mellitus , Holoprosencefalia , Humanos , Diabetes Mellitus/epidemiología , Diabetes Mellitus/etiología , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Holoprosencefalia/epidemiología , Holoprosencefalia/etiología , Contaminación de AlimentosRESUMEN
A G2P0, 24-year-old woman presented at 17 weeks 3 days gestation for a fetal anatomy scan. Ultrasound identified bilateral upper and lower extremity ectrodactyly, semilobar holoprosencephaly, midface hypoplasia, and cleft lip and palate. Amniocentesis for a chromosome microarray demonstrated no significant copy number changes. Whole exome sequencing was subsequently completed, which revealed a de novo, likely pathogenic variant in FGFR1, c.2044G>A (D682N), consistent with FGFR1-related Hartsfield syndrome. This case highlights the first presumed molecularly confirmed prenatal diagnosis of Hartsfield syndrome and identifies a new pathogenic variant.
Asunto(s)
Labio Leporino , Fisura del Paladar , Holoprosencefalia , Embarazo , Femenino , Humanos , Adulto Joven , Adulto , Labio Leporino/diagnóstico por imagen , Labio Leporino/genética , Fisura del Paladar/diagnóstico por imagen , Fisura del Paladar/genética , Holoprosencefalia/diagnóstico , Amniocentesis , Diagnóstico PrenatalRESUMEN
Mutations in SHH and several other genes encoding components of the Hedgehog signaling pathway have been associated with holoprosencephaly syndromes, with craniofacial anomalies ranging in severity from cyclopia to facial cleft to midfacial and mandibular hypoplasia. Studies in animal models have revealed that SHH signaling plays crucial roles at multiple stages of craniofacial morphogenesis, from cranial neural crest cell survival to growth and patterning of the facial primordia to organogenesis of the palate, mandible, tongue, tooth, and taste bud formation and homeostasis. This article provides a summary of the major findings in studies of the roles of SHH signaling in craniofacial development, with emphasis on recent advances in the understanding of the molecular and cellular mechanisms regulating the SHH signaling pathway activity and those involving SHH signaling in the formation and patterning of craniofacial structures.
Asunto(s)
Proteínas Hedgehog , Holoprosencefalia , Animales , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Cresta Neural/metabolismo , Holoprosencefalia/genética , Holoprosencefalia/metabolismo , Morfogénesis/genética , Transducción de Señal/genéticaRESUMEN
Vision is likely our most prominent sense and a correct development of the eye is at its basis. Early eye development is tightly connected to the development of the forebrain. A single eye field and the prospective telencephalon are situated within the anterior neural plate (ANP). During normal development, both domains are split and consecutively, two optic vesicles and two telencephalic lobes emerge. If this process is hampered, the domains remain condensed at the midline. The resulting developmental disorder is termed holoprosencephaly (HPE). The typical ocular finding associated with intense forms of HPE is cyclopia. However, also anophthalmia and coloboma can be associated with HPE. Here, we report that a correct balance of Bone morphogenetic proteins (BMPs) and their antagonists are important for forebrain and eye field cleavage. Experimental induction of a BMP ligand results in a severe form of HPE showing anophthalmia. We identified a dysmorphic forebrain containing retinal progenitors, which we termed crypt-oculoid. Optic vesicle evagination is impaired due to a loss of rx3 and, consecutively, of cxcr4a. Our data further suggest that the subduction of prospective hypothalamic cells during neurulation and neural keel formation is affected by the induction of a BMP ligand.
Asunto(s)
Anoftalmos , Proteínas Morfogenéticas Óseas , Holoprosencefalia , Animales , Proteínas Morfogenéticas Óseas/metabolismo , Regulación del Desarrollo de la Expresión Génica , Ligandos , Estudios Prospectivos , Factores de Transcripción/metabolismo , Pez Cebra/metabolismoRESUMEN
BACKGROUND: Severe macrocephaly can still be found in developing countries. This condition is usually caused by neglected hydrocephalus and can cause a lot of morbidities. Cranial vault reconstruction cranioplasty is the main treatment option for severe macrocephaly. Holoprosencephaly is often seen with features of microcephaly. Hydrocephalus should be considered as the main cause in HPE patients with features of macrocephaly. In this report, we present a rare case of cranial vault reduction cranioplasty procedure in patient with severe macrocephaly due to holoprosencephaly and subdural hygroma. CASE DESCRIPTION: A 4-year-10-month-old Indonesian boy was admitted with head enlargement since birth. He had a history of VP shunt placement when he was 3 months old. But the condition was neglected. Preoperative head CT showed massive bilateral subdural hygroma that compressed brain parenchyma caudally. From the craniometric calculation, the occipital frontal circumference was 70.5 cm with prominent vertex expansion, the distance between nasion to inion was 11.91 cm and the vertical height was 25.59 cm. The preoperative cranial volume was 24.611 cc. The patient underwent subdural hygroma evacuation and cranial vault reduction cranioplasty. The postoperative cranial volume was 10.468 cc. CONCLUSION: Subdural hygroma can be a rare cause of severe macrocephaly in holoprosencephaly patients. Cranial vault reduction cranioplasty and subdural hygroma evacuation is still the main treatment option. Our procedure successfully reduces significant cranial volume (57.46% volume reduction).
Asunto(s)
Holoprosencefalia , Hidrocefalia , Megalencefalia , Efusión Subdural , Masculino , Humanos , Lactante , Holoprosencefalia/complicaciones , Efusión Subdural/etiología , Cráneo/diagnóstico por imagen , Cráneo/cirugía , Megalencefalia/complicaciones , Megalencefalia/diagnóstico por imagen , Megalencefalia/cirugía , Hidrocefalia/cirugíaRESUMEN
BACKGROUND: Diprosopus is a rare malformation of still unclear aetiology. It describes a laterally double faced monocephalic and single-trunk individual and has to be distinguished from the variant Janus type diprosopus. RESULTS: We examined seven double-faced foetuses, five showing true diprosopus, and one each presenting as monocephalic Janiceps and parasitic conjoined twins. Four of the foetuses presented with (cranio)rachischisis, and two had secondary hydrocephaly. Three foetuses showed cerebral duplication with concordant holoprosencephaly, Dandy-Walker cyst and/or intracranial anterior encephalocele. In the Janiceps twins, cerebral duplication was accompanied by cerebral di-symmetry. In the parasitic twins the cyclopic facial aspects were suggestive of concordant holoprosencephaly. In one of the true diprosopus cases, pregnancy was achieved after intracytoplasmic sperm injection. Whole-exome sequencing, perfomed in one case, did not reveal any possible causative variants.The comparison of our double-faced foetuses to corresponding artistic representations from the Tlatilco culture allowed retrospective assignment of hairstyles to brain malformations. CONCLUSION: Brain malformations in patients with diprosopus may not be regarded as an independent event but rather as a sequel closely related to the duplication of the notochord and neural plate and as a consequence of the cerebral and associated craniospinal structural instabilities.
Asunto(s)
Holoprosencefalia , Gemelos Siameses , Embarazo , Femenino , Humanos , Masculino , Holoprosencefalia/genética , Museos , Estudios Retrospectivos , Semen , EncéfaloRESUMEN
OBJECTIVE: To evaluate radiological (gestational and perinatal) and neonatal signs of patients with Patau syndrome and semilobar holoprosencephaly, as well as to report the association of both pathologies. CASE DESCRIPTION: This case report is about a female infant, born at term with trisomy of the chromosome 13 and semilobar holoprosencephaly, with thalamic fusion and a single cerebral ventricle, in addition to several other changes that worsened the patient's prognosis. COMMENTS: Chromosome 13 trisomy is a genetic alteration that leads to the symptoms that determines Patau syndrome. In this syndrome, cardiovascular, urogenital, central nervous system, facial structure and intellectual impairment are common, in addition to problems in limb formation, such as decreased humerus and femur length, polydactyly, hypotelorism and low ear implantation. It is estimated, however, that holoprosencephaly is present in only 24 to 45% of the patients with trisomy 13.
Asunto(s)
Holoprosencefalia , Polidactilia , Recién Nacido , Embarazo , Lactante , Humanos , Femenino , Holoprosencefalia/diagnóstico , Holoprosencefalia/diagnóstico por imagen , Síndrome de la Trisomía 13/complicaciones , Síndrome de la Trisomía 13/diagnóstico , Trisomía , Polidactilia/complicaciones , Polidactilia/diagnóstico , Polidactilia/genética , Mutación , Cromosomas Humanos Par 13RESUMEN
During embryonic development, the forebrain roof plate undergoes invagination, leading to separation of the cerebral hemispheres. Any defects in this process, in humans, lead to middle interhemispheric holoprosencephaly (MIH-HPE). In this study, we have identified a previously unreported downstream mediator of retinoic acid (RA) signaling, CNKSR2, which is expressed in the forebrain roof plate in the chick embryo. Knockdown of CNKSR2 affects invagination, cell proliferation and patterning of the roof plate, similar to the phenotypes observed upon inhibition of RA signaling. We further demonstrate that CNKSR2 functions by modulating the Ras/Raf/MEK signaling. This appears to be crucial for patterning of the forebrain roof plate and its subsequent invagination, leading to the formation of the cerebral hemispheres. Thus, a set of novel molecular players have been identified that regulate the morphogenesis of the avian forebrain.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Holoprosencefalia , Prosencéfalo , Tretinoina , Animales , Embrión de Pollo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Holoprosencefalia/genética , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Prosencéfalo/embriología , Tretinoina/metabolismoRESUMEN
OBJECTIVE: To assess the value of chromosomal microarray analysis (CMA) for the diagnosis of fetuses with anomalies of the central nervous system (CNS) and summarize the outcome of the pregnancies and follow-up. METHODS: A total of 636 fetuses from June 2014 to December 2020 who were referred to the Prenatal Diagnosis Center of Nanjing Drum Tower Hospital due to abnormal CNS prompted by ultrasound were selected as the research subjects. Based on the ultrasound findings, the fetuses were divided into ventricular dilatation group (n = 441), choroid plexus cyst group (n = 41), enlarged posterior fossa group (n = 42), holoprosencephaly group (n = 15), corpus callosum hypoplasia group (n = 22), and other anomaly group (n = 75). Meanwhile, they were also divided into isolated (n = 504) and non-isolated (n = 132) groups based on the presence of additional abnormalities. Prenatal samples (amniotic fluid/chorionic villi/umbilical cord blood) or abortus tissue were collected for the extraction of genomic DNA and CMA assay. Outcome of the pregnancies and postnatal follow-up were summarized and subjected to statistical analysis. RESULTS: In total 636 fetuses with CNS anomalies (including 89 abortus tissues) were included, and 547 cases were followed up. The overall detection rate of CMA was 11.48% (73/636). The detection rates for the holoprosencephaly group, ACC group, choroid plexus cyst group, enlarged posterior fossa group, ventricular dilatation group and other anomaly group were 80% (12/15), 31.82% (7/22), 19.51% (8/41), 14.29% (6/42), 7.48% (33/441) and 9.33% (7/75), respectively. Compared with the isolated CNS anomaly group, the detection rate for the non-isolated CNS anomaly group was significantly higher (6.35% vs. 31.06%) (32/504 vs. 41/132) (χ² = 62.867, P < 0.001). Follow up showed that, for 52 fetuses with abnormal CMA results, 51 couples have opted induced labor, whilst 1 was delivered at full term with normal growth and development. Of the 434 fetuses with normal CMA results, 377 were delivered at full term (6 had developmental delay), and 57 couples had opted induced labor. The rate of adverse pregnancy outcome for non-isolated CNS abnormal fetuses was significantly higher than that of isolated CNS abnormal fetuses (26.56% vs. 10.54%) (17/64 vs. 39/370) (χ² = 12.463, P < 0.001). CONCLUSION: Fetuses with CNS anomaly should be tested with CMA to determine the genetic cause. Most fetuses with negative CMA result have a good prognosis, but there is still a possibility for a abnormal neurological phenotype. Fetuses with CNS abnormalities in conjunct with other structural abnormalities are at increased risk for adverse pregnancy outcomes.
Asunto(s)
Enfermedades del Sistema Nervioso Central , Quistes , Holoprosencefalia , Malformaciones del Sistema Nervioso , Femenino , Embarazo , Humanos , Diagnóstico Prenatal/métodos , Sistema Nervioso Central , Feto/anomalías , Malformaciones del Sistema Nervioso/diagnóstico por imagen , Malformaciones del Sistema Nervioso/genética , Análisis por Micromatrices , Aberraciones Cromosómicas , Ultrasonografía Prenatal/métodosRESUMEN
Congenital hypopituitarism is a genetically heterogeneous condition that is part of a spectrum disorder that can include holoprosencephaly. Heterozygous mutations in SIX3 cause variable holoprosencephaly in humans and mice. We identified two children with neonatal hypopituitarism and thin pituitary stalk who were doubly heterozygous for rare, likely deleterious variants in the transcription factors SIX3 and POU1F1. We used genetically engineered mice to understand the disease pathophysiology. Pou1f1 loss-of-function heterozygotes are unaffected; Six3 heterozygotes have pituitary gland dysmorphology and incompletely ossified palate; and the Six3+/-; Pou1f1+/dw double heterozygote mice have a pronounced phenotype, including pituitary growth through the palate. The interaction of Pou1f1 and Six3 in mice supports the possibility of digenic pituitary disease in children. Disruption of Six3 expression in the oral ectoderm completely ablated anterior pituitary development, and deletion of Six3 in the neural ectoderm blocked the development of the pituitary stalk and both anterior and posterior pituitary lobes. Six3 is required in both oral and neural ectodermal tissues for the activation of signaling pathways and transcription factors necessary for pituitary cell fate. These studies clarify the mechanism of SIX3 action in pituitary development and provide support for a digenic basis for hypopituitarism.
Asunto(s)
Holoprosencefalia , Hipopituitarismo , Niño , Humanos , Heterocigoto , Hipopituitarismo/genética , Factores de Transcripción/genética , Mutación , Hormonas Hipofisarias/genética , Factor de Transcripción Pit-1/genéticaRESUMEN
Hedgehog acyltransferase gene (HHAT)-associated Nivelon-Nivelon-Mabile syndrome (NNMS) is a rare genetic disorder of multiple system involvement with microcephaly, central nervous system malformations, skeletal dysplasia, and 46,XY sex reversal. Other variable and inconsistent features reported in this disorder are muscle spasms, facial dysmorphism, prenatal onset growth restriction, microphthalmia, and holoprosencephaly. This is the sixth postnatal reported patient with biallelic variants in HHAT gene, who presented with microcephaly, short stature, muscle hypertrophy, muscle spasms, and facial dysmorphism. The most prominent and presenting finding in this patient were muscle hypertrophy and muscle spasms which had a clinical response to phenytoin and acetazolamide treatment. Our report emphasizes the phenotypic variability of NNMS and further reiterates muscle spasms as an important clinical manifestation of this extremely rare condition.