Nneamaka B. Agochukwu

Impact of genetics on the diagnosis and clinical management of syndromic craniosynostoses

PurposeMore than 60 different mutations have been identified to be causal in syndromic forms of craniosynostosis. The majority of these mutations occur in the fibroblast growth factor receptor 2 gene (FGFR2). The clinical management of syndromic craniosynostosis varies based on the particular causal mutation. Additionally, the diagnosis of a patient with syndromic craniosynostosis is based on the clinical presentation, signs, and symptoms. The understanding of the hallmark features of particular syndromic forms of craniosynostosis leads to efficient diagnosis, management, and long-term prognosis of patients with syndromic craniosynostoses.MethodsA comprehensive literature review was done with respect to the major forms of syndromic craniosynostosis and additional less common FGFR-related forms of syndromic craniosynostosis. Additionally, information and data gathered from studies performed in our own investigative lab (lab of Dr. Muenke) were further analyzed and reviewed. A literature review was also performed with regard to the genetic workup and diagnosis of patients with craniosynostosis.ResultsPatients with Apert syndrome (craniosynostosis syndrome due to mutations in FGFR2) are most severely affected in terms of intellectual disability, developmental delay, central nervous system anomalies, and limb anomalies. All patients with FGFR-related syndromic craniosynostosis have some degree of hearing loss that requires thorough initial evaluations and subsequent follow-up.ConclusionsPatients with syndromic craniosynostosis require management and treatment of issues involving multiple organ systems which span beyond craniosynostosis. Thus, effective care of these patients requires a multidisciplinary approach.

De novo deletion of chromosome 20q13.33 in a patient with tracheo-esophageal fistula, cardiac defects and genitourinary anomalies implicates GTPBP5 as a candidate gene.

BACKGROUND Tracheo-esophageal fistula (TEF) with/or without esophageal atresia (EA) is a common congenital malformation that is often accompanied by other anomalies. The causes of this condition are thought to be heterogeneous but are overall not well understood. CASE REPORT We identified a patient with a TEF/EA, as well as cardiac and genitourinary anomalies, who was found to have a 0.7 Mb de novo deletion of chromosome 20q13.33. One gene within the deleted interval, GTPBP5, is of particular interest as a candidate gene. CONCLUSIONS GTPBP5 bears further study as a cause of TEF/EA accompanied by other malformations. Birth Defects Research (Part A) 2011.

Palatal and oral manifestations of Muenke syndrome (FGFR3-related craniosynostosis).

Abstract Although Muenke syndrome is the most common syndromic form of craniosynostosis, the frequency of oral and palatal anomalies including high-arched palate, cleft lip with or without cleft palate has not been documented in a patient series of Muenke syndrome to date. Further, to our knowledge, cleft lip and palate has not been reported yet in a patient with Muenke syndrome (a previous patient with isolated cleft palate has been reported). This study sought to evaluate the frequency of palatal anomalies in patients with Muenke syndrome through both a retrospective investigation and literature review. A total of 21 patients who met criteria for this study were included in the retrospective review. Fifteen patients (71%) had a structural anomaly of the palate. Cleft lip and palate was present in 1 patient (5%). Other palatal findings included high-arched hard palate in 14 patients (67%). Individuals with Muenke syndrome have the lowest incidence of cleft palate among the most common craniosynostosis syndromes. However, high-arched palate in Muenke syndrome is common and may warrant clinical attention, as these individuals are more susceptible to recurrent chronic otitis media with effusion, dental malocclusion, and hearing loss.

Talocalcaneal Coalition in Muenke Syndrome: Report of a patient, review of the literature in FGFR-related craniosynostoses, and consideration of mechanism

Muenke syndrome is an autosomal dominant craniosynostosis syndrome resulting from a defining point mutation in the Fibroblast Growth Factor Receptor3 (FGFR3) gene. Muenke syndrome is characterized by coronal craniosynostosis (bilateral more often than unilateral), hearing loss, developmental delay, and carpal and/or tarsal bone coalition. Tarsal coalition is a distinct feature of Muenke syndrome and has been reported since the initial description of the disorder in the 1990s. Although talocalcaneal coalition is the most common tarsal coalition in the general population, it has never previously been reported in a patient with Muenke syndrome. We present a 7‐year‐old female patient with Muenke syndrome and symptomatic talocalcaneal coalition. She presented at the age of 7 with limping, tenderness and pain in her right foot following a fall and strain of her right foot. She was treated with ibuprofen, shoe inserts, a CAM walker boot, and stretching exercises without much improvement in symptoms. A computed tomography (CT) scan revealed bilateral talocalcaneal coalitions involving the middle facet. She underwent resection of the talocalcaneal coalitions, remaining pain‐free post‐operatively with an improvement in her range of motion, gait, and mobility. This report expands the phenotype of tarsal coalition in Muenke syndrome to include talocalcaneal coalition. A literature review revealed a high incidence of tarsal coalition in all FGFR related craniosynostosis syndromes when compared to the general population, a difference that is statistically significant. The most common articulation involved in all syndromic craniosynostoses associated with FGFR mutations is the calcaneocuboid articulation.

Hearing Loss in Syndromic Craniosynostoses: Introduction and Consideration of Mechanisms

PURPOSE There are a number of craniosynostosis syndromes with hearing loss-including Muenke, Apert, Pfeiffer, Crouzon, Beare-Stevenson, Crouzon with acanthosis nigricans, and Jackson-Weiss syndromes-that result from mutations in the fibroblast growth factor receptor (FGFR) genes. Studies of FGFRs and their ligands, fibroblast growth factors (FGFs), have revealed clues to the precise contribution of aberrant FGFR signaling to inner ear morphogenesis and the hearing loss encountered in craniosynostoses. The purpose of this article is to review basic studies of FGFRs with emphasis on their function and expression in the inner ear and surrounding structures. METHOD A Medline search was performed to find basic science articles regarding FGFR, their ligands, and their expression and relevant mouse models. Additional items searched included clinical descriptions and studies of individuals with FGFR-related craniosynostosis syndromes. RESULTS The FGF signaling pathway is essential for the morphogensis and proper function of the inner ear and auditory sensory epithelium. CONCLUSION The variable auditory phenotypes seen in individuals with Muenke syndrome may have a genetic basis, likely due to multiple interacting factors in the genetic environment or modifying factors. Further analysis and studies of mouse models of Muenke syndrome, in particular, may provide clues to the specific effects of the defining mutation in FGFR3 in the inner ear not only at birth but also into adulthood. In particular, investigations into these models may give insight into the variable expression and incomplete penetrance of this phenotype.

Hearing loss in syndromic craniosynostoses: Otologic manifestations and clinical findings

OBJECTIVE This review addresses hearing loss as it occurs and has been reported in Muenke syndrome as well as six additional FGFR related craniosynostosis syndromes (Apert syndrome, Pfeiffer syndrome, Crouzon syndrome, Beare-Stevenson syndrome, Crouzon syndrome with acanthosis nigricans, and Jackson-Weiss syndrome. DATA SOURCES Pub-Med, Medline, Cochrane Database, Science Direct, NLM Catalog. REVIEW METHODS A Medline search was conducted to find all reported cases of the 7 FGFR related syndromic craniosynostosis. Special attention was paid to literature that reported hearing findings and the audiology literature. RESULTS Hearing loss occurs in variable percentage as a component part of all FGFR related craniosynostosis syndromes. Our literature review revealed the following incidences of hearing loss in FGFR craniosynostoses: 61% in Muenke syndrome, 80% in Apert Syndrome, 92% in Pfeiffer syndrome, 74% in Crouzon syndrome, 68% in Jackson Weiss syndrome, 4% in Beare Stevenson syndrome and 14% in Crouzon syndrome with Acanthosis Nigricans. The majority of the hearing loss is a conductive hearing loss, with the exception of Muenke syndrome where the majority of patients have a sensorineural hearing loss and Crouzon syndrome where almost half of patients have a pure or component of sensorineural hearing loss. CONCLUSION This manuscript presents a diagnostic and management algorithm for patients with syndromic craniosynostosis. It will aid clinicians in treating these patients and further, the recognition of a possible syndrome in patients with hearing loss who also have syndromic features.

Executive Function and Adaptive Behavior in Muenke Syndrome.

OBJECTIVE To investigate executive function and adaptive behavior in individuals with Muenke syndrome using validated instruments with a normative population and unaffected siblings as controls. STUDY DESIGN Participants in this cross-sectional study included individuals with Muenke syndrome (P250R mutation in FGFR3) and their mutation-negative siblings. Participants completed validated assessments of executive functioning (Behavior Rating Inventory of Executive Function [BRIEF]) and adaptive behavior skills (Adaptive Behavior Assessment System, Second Edition [ABAS-II]). RESULTS Forty-four with a positive FGFR3 mutation, median age 9 years, range 7 months to 52 years were enrolled. In addition, 10 unaffected siblings served as controls (5 males, 5 females; median age, 13 years; range, 3-18 years). For the General Executive Composite scale of the BRIEF, 32.1% of the cohort had scores greater than +1.5 SD, signifying potential clinical significance. For the General Adaptive Composite of the ABAS-II, 28.2% of affected individuals scored in the 3rd-8th percentile of the normative population, and 56.4% were below the average category (<25th percentile). Multiple regression analysis did not identify craniosynostosis as a predictor of BRIEF (P = .70) or ABAS-II scores (P = .70). In the sibling pair analysis, affected siblings performed significantly poorer on the BRIEF General Executive Composite and the ABAS-II General Adaptive Composite. CONCLUSION Individuals with Muenke syndrome are at an increased risk for developing adaptive and executive function behavioral changes compared with a normative population and unaffected siblings.

Epilepsy in Muenke syndrome: FGFR3-related craniosynostosis.

Epilepsy, a neurologic disorder characterized by the predisposition to recurrent unprovoked seizures, is reported in more than 300 genetic syndromes. Muenke syndrome is an autosomal-dominant craniosynostosis syndrome characterized by unilateral or bilateral coronal craniosynostosis, hearing loss, intellectual disability, and relatively subtle limb findings such as carpal bone fusion and tarsal bone fusion. Muenke syndrome is caused by a single defining point mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. Epilepsy rarely occurs in individuals with Muenke syndrome, and little detail is reported on types of epilepsy, patient characteristics, and long-term outcomes. We present seven patients with Muenke syndrome and seizures. A review of 789 published cases of Muenke syndrome, with a focus on epilepsy and intracranial anomalies in Muenke syndrome, revealed epilepsy in six patients, with intracranial anomalies in five. The occurrence of epilepsy in Muenke syndrome within our cohort of 58 patients, of whom seven manifested epilepsy, and the intracranial anomalies and epilepsy reported in the literature, suggest that patients with Muenke syndrome may be at risk for epilepsy and intracranial anomalies. Furthermore, the impact of Muenke syndrome on the central nervous system may be greater than previously thought.

Genetic-environmental interaction in a unique case of Muenke syndrome with intracranial hypertension

Craniosynostosis, the premature fusion of one of more of the cranial sutures, is relatively common, with an incidence of approximately 1 in 3,000 live births [3]. Although craniosynostosis typically occurs in an isolated manner, without accompanying anomalies, it is also a feature of more than 150 genetic syndromes, the most common of which is Muenke syndrome [4, 15, 19]. Of all patients with craniosynostosis, 8% are estimated to have Muenke syndrome; 24% of patients with craniosynostosis and a known genetic cause have Muenke syndrome [15, 19, 29]. Muenke syndrome is an autosomal dominant craniosynostosis syndrome due to the defining point mutation, c.749C>G, in the FGFR3 gene, resulting in p.Pro250Arg [1, 16]. The condition is characterized by coronal craniosynostosis (bilateral more often than unilateral), carpal and/or tarsal bone fusion, hearing loss, and developmental delay. Following surgical treatment of the craniosynostosis, individuals with Muenke syndrome are five times more likely than individuals with non-syndromic craniosynostosis to need transcranial reoperation for raised intracranial pressure [28]. Vitamin A, which is necessary for the synthesis of visual pigments and is an important component of membrane stability, is obtained from two sources: preformed vitamin A (derived from animal sources) and provitamin A (from carotenoids, fruits, and vegetables) [11, 12]. Preformed vitamin A is efficiently absorbed and used by humans at absorption rates of 70–90%. Provitamin A, derived from carotenoids and plant foods, is absorbed much less efficiently, at rates of 20–30% [12]. Vitamin A toxicity has traditionally been thought of as being unlikely to result from provitamin A due to its relatively poor absorption efficiency and the fact that the conversion of carotenoids to vitamin A is highly regulated. For this reason, carotenemia, a term used to describe excess levels of carotene (a source of provitamin A) in the blood, has been described as being benign aside from the yellow pigmentation of skin. There have been several reports of benign carotenemia secondary to carrot ingestion, the most common cause of carotenemia, as well as dietary dried seaweed, green beans, and nutrient supplementation [14, 17, 26, 27]. The association of vitamin A with intracranial hypertension is well established. In one study of idiopathic intracranial hypertension, affected patients had significant elevation of serum retinal (a derivative of vitamin A) compared to controls [13]. Vitamin A is also one of the known contributors to the pathophysiology of idiopathic intracranial hypertension, although its exact role has yet to be elucidated [8]. Hypervitaminosis A has also been associated with hydrocephalus, a known structural cause of increased intracranial pressure [22].