 | This article may incorporate text from a large language model .(December 2024) |
| Bosma arhinia microphthalmia syndrome | |
|---|---|
| Other names |
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| Specialty | Medical genetics |
| Symptoms | |
| Causes | Mutations in SMCHD1 gene |
Bosma arhinia microphthalmia ayndrome' (BAMS), Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome, or just Bosma syndrome is a rare genetic disorder characterized by nasal and ocular abnormalities, often accompanied by endocrine dysfunction.
The typical indicator of BAMS is arrhinia, characterized by the complete absence of an external nose or, in some cases, a severely underdeveloped (hypoplastic) nose. [1] [2] This is often accompanied by the absence of olfactory bulb, leading to impaired smell (hyposmia or anosmia) and taste (ageusia). [1] Patients typically exhibit microphthalmia (abnormally small eyeballs) or anophthalmia (absence of eyeballs), resulting in severe vision impairment or blindness. [2] [3] Additional eye abnormalities may include colobomas, cataracts, and nasolacrimal duct obstruction. [1] Common craniofacial abnormalities include a high-arched or cleft palate, absence of paranasal sinuses, choanal atresia, and a hypoplastic maxilla. Some patients may also present with external ear abnormalities. [1] [2] BAMS is associated with hypogonadotropic hypogonadism, leading to absent or delayed puberty and sexual development. This can manifest as underdeveloped genitals in males and lack of breast development or menstruation in females. [1] Despite the severe craniofacial abnormalities, patients with BAMS typically have normal cognition and intellectual abilities. [1]
Bosma arhinia microphthalmia syndrome is primarily caused by mutations in the SMCHD1 gene, which encodes a protein involved in gene silencing during embryonic development and is particularly important to the development of the head and facial features. [4] [2] [5] These mutations are typically de novo and occur in the N-terminal GHKL-type ATPase domain, suggesting a gain-of-function effect that disrupts normal nasal and ocular development. [6] [7] BAMS follows an autosomal dominant inheritance pattern, meaning a single mutated copy of the SMCHD1 gene can cause the disorder. [2] While SMCHD1 is the primary gene implicated, other unknown genetic factors may also contribute to the condition's severity. [2] [5]
The SMCHD1 gene plays a critical role in craniofacial development by regulating chromatin structure and gene expression during embryogenesis. [8] Disruption in these processes due to SMCHD1 mutations can lead to the developmental anomalies observed in BAMS. [8] [9]
Bosma arhinia microphthalmia syndrome is typically diagnosed at birth due to its distinct facial features, such as the absence of the nose and small or absent eyes. The initial diagnosis is primarily based on a thorough physical examination. [5] [2] However, genetic testing is needed to confirm the diagnosis by identifying mutations in the SMCHD1 gene. The SMCHD1 gene is analyzed using techniques such as next-generation sequencing to detect pathogenic variants that are characteristic of BAMS. [7] Such analyses are needed to distinguish BAMS from other syndromes that present with similar craniofacial abnormalities, such as CHARGE syndrome or Treacher Collins syndrome. [3] [1] [10] Due to potential endocrine dysfunctions associated with BAMS, hormonal evaluations may be conducted to assess for hypogonadotropic hypogonadism, which is common in affected individuals. [5] [2]
Treatment is primarily symptomatic and focuses on addressing the needs of each individual. Given the complexity and rarity of the syndrome, a multidisciplinary approach is often required, involving specialists such as pediatricians, endocrinologists, ophthalmologists, and craniofacial surgeons. Surgical reconstruction can be considered to improve both function and appearance of the nose. This may involve multiple staged surgeries to create a nasal structure that allows for normal breathing and enhances facial aesthetics. Advances in technology, such as 3D printing, have enhanced the ability to create custom nasal implants, improving cosmetic outcomes. [11] [12] For individuals with microphthalmia or anophthalmia, ocular prosthesis can be used to improve cosmetic appearance. In cases where some vision is present, ophthalmologists may provide interventions to maximize visual function. [3] [12]
Individuals with BAMS experience hypogonadotropic hypogonadism due to disrupted gonadotropin-releasing hormone (GnRH) neurons. Hormone therapy can help manage this condition by supplementing deficient hormones, thereby supporting normal pubertal development and fertility when appropriate. [4] [10] Given the visible nature of craniofacial differences and potential social challenges, psychological support and counseling are often recommended for patients and their families. [5] [12] Genetic counseling is also recommended to provide information about the hereditary aspects of BAMS. [12] Regular follow-up care is essential to monitor growth, development, and any emerging complications. This includes managing associated comorbidities such as vitamin D deficiency, which can lead to osteoporosis if untreated. [4] [1]
Bosma arhinia microphthalmia syndrome is an extremely rare genetic disorder, with fewer than 100 reported cases worldwide. [1] Due to its rarity, precise epidemiological data, including incidence and prevalence rates, are not well established. The condition appears to affect both males and females equally, although specific gender-based prevalence data are lacking. BAMS has been documented in various populations globally, but the distribution of cases does not suggest any particular ethnic or geographic predisposition. The rarity of the syndrome means that it often goes unreported in many regions, contributing to the difficulty in gathering comprehensive epidemiological data. [1]
Septo-optic dysplasia (SOD), known also as de Morsier syndrome, is a rare congenital malformation syndrome that features a combination of the underdevelopment of the optic nerve, pituitary gland dysfunction, and absence of the septum pellucidum . Two or more of these features need to be present for a clinical diagnosis—only 30% of patients have all three. French-Swiss doctor Georges de Morsier first recognized the relation of a rudimentary or absent septum pellucidum with hypoplasia of the optic nerves and chiasm in 1956.
Kallmann syndrome (KS) is a genetic disorder that prevents a person from starting or fully completing puberty. Kallmann syndrome is a form of a group of conditions termed hypogonadotropic hypogonadism. To distinguish it from other forms of hypogonadotropic hypogonadism, Kallmann syndrome has the additional symptom of a total lack of sense of smell (anosmia) or a reduced sense of smell. If left untreated, people will have poorly defined secondary sexual characteristics, show signs of hypogonadism, almost invariably are infertile and are at increased risk of developing osteoporosis. A range of other physical symptoms affecting the face, hands and skeletal system can also occur.
Microphthalmia, also referred as microphthalmos, is a developmental disorder of the eye in which one or both eyes are abnormally small and have anatomic malformations. Microphthalmia is a distinct condition from anophthalmia and nanophthalmia. Although sometimes referred to as 'simple microphthalmia', nanophthalmia is a condition in which the size of the eye is small but no anatomical alterations are present.
Isolated hypogonadotropic hypogonadism (IHH), also called idiopathic or congenital hypogonadotropic hypogonadism (CHH), as well as isolated or congenital gonadotropin-releasing hormone deficiency (IGD), is a condition which results in a small subset of cases of hypogonadotropic hypogonadism (HH) due to deficiency in or insensitivity to gonadotropin-releasing hormone (GnRH) where the function and anatomy of the anterior pituitary is otherwise normal and secondary causes of HH are not present.
Goldenhar syndrome is a rare congenital defect characterized by incomplete development of the ear, nose, soft palate, lip and mandible on usually one side of the body. Common clinical manifestations include limbal dermoids, preauricular skin tags and strabismus. It is associated with anomalous development of the first branchial arch and second branchial arch.
Arrhinia is the congenital partial or complete absence of the nose at birth. It is an extremely rare condition, with few reported cases in the history of modern medicine. It is generally classified as a craniofacial abnormality.
Craniofrontonasal dysplasia is a very rare X-linked malformation syndrome caused by mutations in the ephrin-B1 gene (EFNB1). Phenotypic expression varies greatly amongst affected individuals, where females are more commonly and generally more severely affected than males. Common physical malformations are: craniosynostosis of the coronal suture(s), orbital hypertelorism, bifid nasal tip, dry frizzy curled hair, longitudinal ridging and/or splitting of the nails, and facial asymmetry.
Anophthalmia is the medical term for the absence of one or both eyes. Both the globe and the ocular tissue are missing from the orbit. The absence of the eye will cause a small bony orbit, a constricted mucosal socket, short eyelids, reduced palpebral fissure and malar prominence. Genetic mutations, chromosomal abnormalities, and prenatal environment can all cause anophthalmia. Anophthalmia is an extremely rare disease and is mostly rooted in genetic abnormalities. It can also be associated with other syndromes.
Papillorenal syndrome is an autosomal dominant genetic disorder marked by underdevelopment (hypoplasia) of the kidney and colobomas of the optic nerve.
Ablepharon macrostomia syndrome (AMS) is an extremely rare, autosomal dominant genetic disorder characterized by abnormal phenotypic appearances that primarily affect the head and face as well as the skull, skin, fingers and genitals. AMS generally results in abnormal ectoderm-derived structures. The most prominent abnormality is the underdevelopment (microblepharon) or absence of eyelids – signifying the ablepharon aspect of the disease – and a wide, fish-like mouth – macrostomia. Recent scholars and surgeons have called into question the naming of the condition as "Ablepharon" on account of recent investigation and histology showing consistent evidence of at least some eyelid tissue. Infants presenting with AMS may also have malformations of the abdominal wall and nipples. Children with AMS might also experience issues with learning development, language difficulties and intellectual disabilities.
Chromodomain-helicase-DNA-binding protein 7 is an ATP-dependent 'chromatin' or 'nucleosome' remodeling factor that in humans is encoded by the CHD7 gene.
Frontonasal dysplasia (FND) is a congenital malformation of the midface. For the diagnosis of FND, a patient should present at least two of the following characteristics: hypertelorism, a wide nasal root, vertical midline cleft of the nose and/or upper lip, cleft of the wings of the nose, malformed nasal tip, encephalocele or V-shaped hair pattern on the forehead. The cause of FND remains unknown. FND seems to be sporadic (random) and multiple environmental factors are suggested as possible causes for the syndrome. However, in some families multiple cases of FND were reported, which suggests a genetic cause of FND.
Leydig cell hypoplasia (LCH), also known as Leydig cell agenesis, is a rare autosomal recessive genetic and endocrine syndrome affecting an estimated 1 in 1,000,000 individuals with XY chromosomes. It is characterized by an inability of the body to respond to luteinizing hormone (LH), a gonadotropin which is normally responsible for signaling Leydig cells of the testicles to produce testosterone and other androgen sex hormones. The condition manifests itself as pseudohermaphroditism, hypergonadotropic hypogonadism, reduced or absent puberty, and infertility.
Gonadotropin-releasing hormone (GnRH) insensitivity also known as Isolated gonadotropin-releasing hormone (GnRH)deficiency (IGD) is a rare autosomal recessive genetic and endocrine syndrome which is characterized by inactivating mutations of the gonadotropin-releasing hormone receptor (GnRHR) and thus an insensitivity of the receptor to gonadotropin-releasing hormone (GnRH), resulting in a partial or complete loss of the ability of the gonads to synthesize the sex hormones. The condition manifests itself as isolated hypogonadotropic hypogonadism (IHH), presenting with symptoms such as delayed, reduced, or absent puberty, low or complete lack of libido, and infertility, and is the predominant cause of IHH when it does not present alongside anosmia.
Hypogonadotropic hypogonadism (HH), is due to problems with either the hypothalamus or pituitary gland affecting the hypothalamic-pituitary-gonadal axis. Hypothalamic disorders result from a deficiency in the release of gonadotropic releasing hormone (GnRH), while pituitary gland disorders are due to a deficiency in the release of gonadotropins from the anterior pituitary. GnRH is the central regulator in reproductive function and sexual development via the HPG axis. GnRH is released by GnRH neurons, which are hypothalamic neuroendocrine cells, into the hypophyseal portal system acting on gonadotrophs in the anterior pituitary. The release of gonadotropins, LH and FSH, act on the gonads for the development and maintenance of proper adult reproductive physiology. LH acts on Leydig cells in the male testes and theca cells in the female. FSH acts on Sertoli cells in the male and follicular cells in the female. Combined this causes the secretion of gonadal sex steroids and the initiation of folliculogenesis and spermatogenesis. The production of sex steroids forms a negative feedback loop acting on both the anterior pituitary and hypothalamus causing a pulsatile secretion of GnRH. GnRH neurons lack sex steroid receptors and mediators such as kisspeptin stimulate GnRH neurons for pulsatile secretion of GnRH.
The fertile eunuch syndrome or Pasqualini syndrome is a cause of hypogonadotropic hypogonadism caused by a luteinizing hormone deficiency. It is characterized by hypogonadism with spermatogenesis. Pasqualini and Bur published the first case of eunuchoidism with preserved spermatogenesis in 1950 in la Revista de la Asociación Médica Argentina. The hypoandrogenism with spermatogenesis syndrome included:
Structural Maintenance of Chromosomes flexible Hinge Domain Containing 1 (SMCHD1) is a protein that in humans is encoded by the SMCHD1 gene. Mutations in SMCHD1 are causative for development of facioscapulohumeral muscular dystrophy type 2 (FSHD2) and Bosma arhinia microphthalmia syndrome (BAMS).
Syndromic microphthalmia is a class of rare congenital anomalies characterized by microphthalmia along with other non-ocular malformations. Syndromic microphthalmia accounts for 60 to 80% of all cases of microphthalmia. Syndromic microphthalmias are caused by mutations in genes related to embryonic craniofacial development, and they are typically classified based on their genetic cause.
Waardenburg anophthalmia syndrome is a rare autosomal recessive genetic disorder which is characterized by either microphthalmia or anophthalmia, osseous synostosis, ectrodactylism, polydactylism, and syndactylism. So far, 29 cases from families in Brazil, Italy, Turkey, and Lebanon have been reported worldwide. This condition is caused by homozygous mutations in the SMOC1 gene, in chromosome 14.
Eric Liao is an American pediatric surgeon-scientist. He specializes in plastic and reconstructive craniofacial surgery, especially in the surgical treatment of cleft lip and palate, rhinoplasty, otoplasty, and nasal reconstruction. Liao's research interests are focused on the genetics and developmental biology that govern facial formation and craniofacial anomalies. He is the founding director of the Center for Craniofacial Innovation at the Children’s Hospital of Philadelphia, the Vice Chair of Academic Affairs in the Department of Surgery, and a Professor of Surgery at the University of Pennsylvania Perelman School of Medicine.