The FG syndrome: Report of a large Italian series

Abstract

Initially described as a rare MCA/MR syndrome occurring only in boys, due to a recessive mutation on the X chromosome , the FG syndrome (FGS) now emerges as a more common disorder also occurring in girls. Based on over 50 reported cases, FGS is associated with developmental delay (especially speech), hypotonia, postnatal onset relative macrocephaly, prominent forehead, frontal hair upsweep, telecanthus, or ocular hypertelorism, thin vermilion border of the upper lip, relatively short fingers with broad thumbs and halluces, persistent fetal fingertip pads, anal anomalies, and/or constipation. Major malformations are rare, and include pyloric stenosis, anal agenesis, cryptorchidism, hypospadias, and congenital heart defects. Abnormal EEGs and seizures have been reported in almost 70% of patients. Brain MRI shows corpus callosum abnormalities associated with dilatation of lateral ventricles and, less frequently, periventricular nodular heterotopias, mild cerebellar defects, and reduced periventricular white matter. Chiari 1 malformation seems to be frequent. The behavior phenotype appears to be characterized by ADHD, and relatively less developed language, fine motor and executive function skills; whereas visual-spatial abilities seem to be a relative strength. Five candidate loci are already known but no gene identified. We describe 25 patients referred to the Stella Maris Institute for evaluation of DD/MR, and diagnosed as FGS. They were between 2 and 15½ years at the first observation. High resolution banding, FRAXA/FRAXE DNA analysis, and subtelomere FISH analysis were performed in all of them, and all had normal results. Thirteen patients were followedup from 6 months to 9 years. Our report focuses on physical, neurological, developmental findings, and natural history of FGS. Experience with our series of patients suggests that the syndrome may be common, and should be routinely considered in the evaluation of children and adolescents with DD/MR. ß

FG syndrome, an X-linked multiple congenital anomaly syndrome: The clinical phenotype and an algorithm for diagnostic testing

“…The clinical features of this US group were analyzed to determine which features to include in the algorithm. The second group was recruited from the patient series reported by Battaglia et al 11 in Italy. This second group of 19 clinically diagnosed Italian patients with FG (13 male patients), also negative for the MED12 mutation, were examined by several authors (A.B., R.D.C., J.G.)…”

Clinical experience in the evaluation of 30 patients with a prior diagnosis of FG syndrome

“…Since the initial description of FGS the clinical spectrum has widened considerably 2 – 5. Features now commonly attributed to FGS include relative macrocephaly, tall and prominent forehead, frontal hair upsweep, abnormal ears, hypertelorism, downslanting palpebral fissures, broad thumbs and halluces, persistent fetal fingertip pads, complete or partial agenesis of the corpus callosum, mental retardation, hypotonia, characteristic behaviour consisting of a friendly, inquisitive, and hyperactive personality with a very short attention span, sensorineural deafness, and constipation.…”

“…As a result, FGS is now considered by some a common disorder 5 7. However, many features reported in FGS, such as constipation, are non-specific and may lead to over diagnosis 8 – 10.…”

X‐linked intellectual disability: Unique vulnerability of the male genome

“…FG syndrome (FGS) initially was described in 1974 by Opitz and Kaveggia as a rare X-linked disorder associated with mental retardation, hypotonia, relative macrocephaly, broad and flat thumbs, and imperforate anus [Opitz and Kaveggia, 1974]. Since the initial description the spectrum of clinical findings attributed to FGS widened considerably [Neri et al, 1984;Thompson and Baraitser, 1987;Opitz et al, 1988;Battaglia et al, 2006]. Features now commonly attributed to FGS include relative macrocephaly, tall and prominent forehead, frontal hair upsweep, abnormal ears, hypertelorism, downslanting palpebral fissures, broad thumbs and halluces, persistent fetal fingertip pads, complete or partial agenesis of the corpus callosum, mental retardation, hypotonia, characteristic behavior consisting of a friendly, inquisitive, and hyperactive personality with a very short attention span, sensorineural deafness, and constipation.…”

“…The wide array of clinical features attributed to FGS and the absence of a specific confirmatory gene test led to relaxation of the diagnostic criteria so that the diagnosis was given to individuals with single or a few overlapping findings [Finocchi et al, 2005;Battaglia et al, 2006]. However, many features in FGS noted earlier, such as constipation, abnormal ears, and hypotonia, are nonspecific, a factor that clearly led to overdiagnosis [Thompson et al, 1985;Fryns et al, 1996;Bohmer et al, 2001].…”