How to Cite this Article: Dentici ML, Mingarelli R, Dallapiccola B. 2011. The difficult nosology of blepharophimosis–mental retardation syndromes: Report on two siblings. Am J Med Genet Part A 155: 459–465.
Blepharophimosis is defined as an abnormal fixed reduction in the vertical distance between the upper and lower eyelids with tight lids and short palpebral fissures [Guercio and Martyn, 2007]. Other periorbital anomalies, including epicanthus inversus and ptosis, are often associated with blepharophimosis, although not required for the finding [Hall et al., 2009]. These anomalies are most commonly features of the autosomal dominant blepharophimosis–ptosis–epicanthus inversus syndrome (BPES) [Zlotogora et al., 1983], caused by a deletion or mutation of the FOXL2 gene at 3q22-23 [Crisponi et al., 2001]. Blepharophimosis may also occur as part of a number of clinically recognized multiple congenital anomaly (MCA) disorders, notably Dubowitz syndrome (DS) [Dubowitz, 1965], Marden–Walker syndrome (MWS) [Marden and Walker, 1966], Toriello–Carey syndrome [Toriello and Carey, 1988], and Smith–Lemli–Opitz syndrome [Smith et al., 1964]. The majority of syndromic patients with blepharophimosis show a variable degree of mental retardation. A particular combination of blepharophimosis and mental retardation (BMR) in two siblings and a parental first cousin allowed Ohdo et al.  to delineate a new autosomal recessive MCA syndrome. Subsequently, several cases have been reported as Ohdo/Ohdo-like syndrome [Say and Barber, 1987; Young and Simpson, 1987; Biesecker, 1991; Clayton-Smith et al., 1994; Melnyk, 1994], widening the spectrum of clinical findings of blepharophimosis–mental retardation syndromes (BMRS), which lately were classified into five subtypes [Verloes et al., 2006]. BMR may also be found in relatively nonspecific developmental anomalies [Cunniff et al., 1998] and in unclassified individuals [Buntinx and Majewski, 1990; de Die-Smulders et al., 1993]. A fraction of these latter patients displays cryptic chromosome rearrangements [Bartholdi et al., 2008; Day et al., 2008; Brancati et al., 2009], further widening the etiology of BMR disorders.
We evaluated two Italian siblings presenting with BMR, striking facial appearance, microcephaly, severe feeding difficulties with gastro-esophageal reflux (GER), poor growth, global psychomotor delay, and absent speech. Additional features included ocular, gastrointestinal and renal anomalies, and with low cholesterol and raised TSH levels in the first sibling, and axial hypotonia, abnormal neurological findings, and low GH levels in the second sib. We reviewed the disorders in which BMR is a cardinal feature, and concluded that both clinical characteristics and inheritance pattern in the present siblings provide a further example of the heterogeneous spectrum of BMRS.
This girl was the first offspring of Caucasian nonconsanguineous parents. Family history was unremarkable. The baby was born after an uneventful pregnancy at 38 weeks of gestation by Cesarean section due to podalic presentation. Birth weight was 2,550 g (3rd centile), length 45 cm (3rd centile), and OFC (occipito-frontal circumference) 31.5 cm (<3rd centile). Apgar scores were 5–8–8 at 1, 5, and 10 min. Physical examination disclosed torticollis resulting in an abnormal posture, submucous cleft palate, and facial dysmorphisms (see below). Additional features included apnea and bradycardia. On the third day of life, a total body X-ray was normal. Severe muscular hypotonia in the newborn period caused difficulties with sucking, leading to prolonged hospitalization and nasogastric tube feeding. Regurgitation and vomiting occurred after feeding, contributing to poor weight gain. Feeding behavior improved in the following years, but at age 6 she was still suffering from GER and constipation. Physical examination at different ages, disclosed a quite distinctive facial gestalt with microcephaly, prominent forehead, sparse eyebrows, blepharophimosis, upward slanted palpebral fissures, unilateral ptosis, epicanthal folds, hypertelorism and dystopia canthorum, midface hypoplasia, long philtrum and mild micrognathia. The ears were low set with over-folded helices, prominent antihelix, and wide antitragus (Fig. 1). Fifth fingers were clinodactylous.
At 5 months submucous cleft palate and left palpebral ptosis were repaired. Ophthalmologic evaluation revealed astigmatism and mild strabismus which were apparently not related with the abnormal neck posture. Fundus oculi was unremarkable. Audiometric evaluation was normal. Tooth eruption in terms of position, structure, and time sequence was normal. An echocardiogram and complete X-ray skeletal survey were normal. An abdominal ultrasound scan revealed gastrectasia, distension of the gall-bladder, and duplication of the right pelvis with ipsilateral lower tract pielectasia. At 3 years of age, a brain MRI disclosed agenesis of the corpus callosum rostrum while the anterior commissure was not appreciable. Routine laboratory analysis were unremarkable with the exception of total cholesterol which was reduced (90 mg/dl, n.v. 120–220 mg/dl), and well responsive to treatment. Measurements of 7- and 8-dehydrocholesterol blood levels were normal. TSH serum concentration was raised (4.5 mIU/L, n.v. 0.30–3.60), with normal serum levels of thyroid hormones. Thyroid ultrasound showed a reduced gland volume. GH was evaluated at different ages and was always within normal lower limits.
Global psychomotor skills were delayed. She sat unsupported at 10 months, crawled at 16 months, and walked at 30 months. Abnormal motor skills were noted with the patient presenting anomalous gross movements. At the last evaluation, at 6 years of age, weight was 14.5 kg, height 100 cm, and OFC 47.5 cm (all <3rd centile). Inner canthal distance (ICD), interpupillary distance (IPD), and palpebral fissures were, respectively, 3.3 cm (+2 SD), 5.8 cm (>97), 24 mm (−2 SD). The girl still had no verbal capacity. She vocalized producing babbling sounds despite continuous speech therapy. She was emotionally attached to her mother and was irritable outside of the family contest.
Chromosome analysis was normal. A high-resolution array-CGH analysis (44K Chip; Agilent Technologies, Walldbronn, Germany) excluded submicroscopic genomic imbalances.
This male sib of Patient 1 was born at 38 weeks of gestation. A mild oligohydramnios was diagnosed in the third trimester; an amniocentesis disclosed a normal karyotype. Birth weight was 2,410 g (3rd centile), length 46 cm (3rd centile), and OFC 30 cm (<3rd centile). Apgar scores were 8 and 9 at 1 and 5 min. Both testes were descended. Persistent feeding difficulties with frequent vomiting and GER were noted soon after the discharge from the neonatal unit, leading to severe failure to thrive. Weight and stature were always below −2 SD. Liquid food refusal persisted until the age of 15 months, while he was still refusing to ingest solid food. Dysmorphic features remained unchanged throughout the observational period of 18 months (Fig. 2). Craniofacial characteristics included microcephaly, blepharophimosis, upward palpebral fissures, hypertelorism, telecanthus, midface hypoplasia, posteriorly rotated ears with over-folded helices, notched in the superior helical portion, prominent antihelices and wide antitragus, triangular nose tip with anteverted nares, long philtrum, high palate, micrognathia. Ectodermal abnormalities included fine sparse hair and eyebrows, thin pale skin and eczema that cleared by the age of 1 year.
Ophthalmological evaluation, renal and thyroid ultrasound, echocardiogram, visual and otoacustic evoked potentials were normal. Timing of dental eruption and shape were normal. A cerebral MRI at 18 months disclosed a markedly reduced pituitary gland and a partial empty sella. All developmental areas were delayed: he sat unsupported at 10 months and at 18 months he still had no expressive language and manifested abnormal motor skills with slow movements. Routine laboratory investigations, including cholesterol levels were normal, while an IGF1 level of 1.5 nmol/L (n.v. 2.2–32.2 nmol/L) was present. At 18 months, a GH curve disclosed a peak of stimulated GH level of 14 ng/ml (n.v. >20 ng/ml) and low ACTH levels. These results prompted a therapy with GH hormone and hydrocortisone.
These two siblings share a constellation of overlapping clinical features including microcephaly, thin hair, sparse eyebrows, blepharophimosis, upward slanted palpebral fissures, hypertelorism, dystopia canthorum, depressed nasal bridge, small triangular nose, anteverted nares, low set posteriorly rotated and dysmorphic ears, micrognathia, and midface hypoplasia. Natural history of this condition was characterized by severe poor growth with feeding difficulties and short stature, psychomotor delay with mental retardation, absent speech and abnormal gross motor movements. Nonspecific neuroradiological anomalies were found in both sibs, including partial agenesis of the corpus callosum and frontal commissure in Patient 1 and pituitary hypoplasia in Patient 2. High-resolution array-CGH detecting CNV as small as 75 kb was performed in the first sib, and excluded submicroscopic genomic rearrangements. This result, together with the negative family history, favors the hypothesis that these patients were affected by an autosomal recessive disorder.
The London Medical Database (Winter–Baraitser dysmorphology database) contains not less than 80 distinct syndromes displaying the main features observed in our sibs, including BMRS. Excluding the genomic conditions and several disorders that may be convincingly ruled out on the basis of the clinical phenotype or associated features, the differential diagnosis was narrowed to only a few conditions, comprising primarily DS. This disorder was suggested when the family was evaluated after the birth of the second newborn. Indeed, these sibs shared a number of features of DS including BMR, microcephaly, broad nasal bridge, micrognathia, growth retardation, feeding difficulties and failure to thrive, ectodermal anomalies, with thin hair and sparse eyebrows. Furthermore, Patient 1 presents with agenesis of the corpus callosum, kidney anomaly, and distension of the gallbladder which are all characteristics reported in DS. However, the characteristic sloping forehead, shallow supraorbital ridges and abnormally modeled and prominent ears were absent and the telecanthus in our patients was too marked to suggest DS [Tsukahara and Opitz, 1996]. At our last evaluation we concluded that DS was unlikely the diagnosis, considering both the global facial gestalt and the coexistence in our patients of additional multisystem anomalies.
Another considered differential diagnostic in the MWS was a heterogenous MCA condition displaying BMR in association with microcephaly, ptosis, telecanthus, cleft palate, severe postnatal growth retardation, and tone abnormalities. The autosomal recessive inheritance in MWS was also in agreement with this suggestion. However, this diagnosis was ruled out, based on the absence of congenital joint contractures and of characteristic immobile/expressionless face in our siblings, both features being considered mandatory of MWS [Williams et al., 1993].
A cholesterol biosynthetic defect in the present patients was debated, based on the abnormally low cholesterol level (90 mg/dl) in Patient 1. Some MCA–mental retardation syndromes caused by inborn errors of cholesterol synthesis have fostered the role of cholesterol metabolism in human development [Porter, 2002]. The prototypic example of these cholesterolopathies is RSH/Smith–Lemli–Opitz syndrome (SLOS), an autosomal recessive disorder due to a deficiency of 7DHC reductase (7DHCR), the final step of the Kandutsch–Russell cholesterol biosynthesis pathway [Kelley and Hennekam, 2000]. SLOS manifests a number of features overlapping with those found in the present siblings, such as failure to thrive, severe growth retardation, hypotonia, and developmental delay/mental retardation. Various facial features could also be consistent with this diagnosis, including microcephaly, blepharophimosis, palpebral ptosis, anteverted nostrils, broad nasal tip, and micrognathia. However, some distinct characteristics of SLS, such as 2–3 syndactyly of the toes and genital anomalies with hypospadias and a hypoplastic scrotum in males were not found in our patients [Dallaire and Fraser, 1969]. SLOS was conclusively excluded by the detection of normal 7-cholesterol precursors levels, 7- and 8-dehydrocholesterol (7-DHC and 8-DHC) in Patient 1 and normal cholesterol in Patient 2. Finally, additional clinical findings such as thickening of the gums or palatal ridges which could suggest a cholesterol storage defect were absent in both sibs.
The need for a clinical categorization of BMRS was raised by Verloes et al.  who proposed a classification into five groups, including: (1) del (3p) syndrome; (2) BMR/Ohdo syndrome, limited to the original family described by Ohdo et al. ; (3) Say–Barber/Biesecker/Young–Simpson syndrome (SBBYS); (4) BMRS, MKB (Maat–Kievit–Brunner) type; (5) BMRS V (Verloes) type. Group 1, which in addition to del(3p) also includes other chromosomal imbalances causative of BMR [Bartholdi et al., 2008; Brancati et al., 2009], was ruled out by high-resolution array-CGH analysis in Case 1. Group 2 is characterized by severe amblyopia, hypoplastic teeth, and heart defect, a constellation of features not present in our siblings. Groups 4 (MKB) and 5 (Verloes) did not apply to our sibs, based on the likely X-linked mode of inheritance and severe epilepsy, absent in these patients.
Differential diagnosis with Group 3 (SBBYS), recently updated into three subtypes [Day et al., 2008], and other overlapping BMR disorders is reported in Table I. Although our patients display a number of clinical features of SBBYS, they are not fitting strictly within any of these categories. The hallmark in our patients was severe growth retardation, which is not characteristic of SBBYS subtype 1 where usually normal growth throughout childhood is expected [Day et al., 2008]. Moreover, dental irregularity, hearing impairment, cardiac defects, and joint hyperextensibility, which are consistent findings in SBBYS subtypes 1 and 2 (Ohdo-like syndrome, OLS), were absent in our siblings. The difficulty in differentiating the present cases with SBBYS subtype 3 (YSS) is due to the clinical and etiological variability of this condition. In SBBYS–YSS, thyroid hypoplasia is a constant feature and was also present in Patient 1. However, absent speech, as observed in our patients, has been recorded only in a minority of YSS individuals [Day et al., 2008]. In addition, facial appearance, which in YSS is reported to change overtime [Verloes et al., 2006], remained unchanged throughout the years in our siblings.
Table I. Comparison of Clinical Features in Dubowitz Syndrome (DS), Marden–Walker Syndrome (MWS), Blepharophimosis–Mental Retardation Syndromes (BMRS)–Say/Barber/Biesecker/Young–Simpson Syndrome (SBBYS), Divided Into Subtype 1 (Severe and Homogenous Phenotype), OLS (Ohdo-Like Syndrome) and YSS (Young–Simpson Syndrome), and Present Patients
Following the classification proposed by Verloes et al. , different genomic imbalances were reported in patients considered affected by YSS [Robinson et al., 2008; Brancati et al., 2009], suggesting that the YSS subtype could be a recurrent phenotype in various submicroscopic imbalances rather than a distinct syndrome. An example was a 3-year-old girl presenting with the typical facial features of YSS associated with dilated cardiomyopathy in whom a microarray analysis disclosed a 5.5 Mb deletion of chromosome 1p36.3 [Robinson et al., 2008]. Similarly, the YSS patient reported by Cavalcant  was found, 20 years later, to be heterozygous for a de novo 3p26.3p25.3 deletion spanning about 10.5 Mb of genomic DNA [Brancati et al., 2009]. The possibility of a cryptic chromosome anomaly was ruled out in our patients by high-resolution microarray CGH analysis, although a 44K microarray can still miss a smaller imbalance or a dominantly acting mutation. Interestingly, the patient of Cavalcanti shared several features with our patients, including facial dysmorphisms and hypothyroidism. The striking similarities between our cases and the patient of Cavalcanti raises the possibility that our patients may be homozygous for a recessive acting gene present within the deleted region of the latter patient. In this sense, the 10.5 Mb 3p26.3p25.3 deletion found in the patient of Cavalcanti may disclose a mutation in a recessive gene on the nondeleted chromosome causative of a subtype of YSS-BMRS, which is “unmasked” by the loss of the second copy by chromosomal deletion. The possibility of an autosomal recessive pattern of inheritance was raised by parental consanguinity in a sporadic YSS patient [Bonthron et al., 1993] and by the recurrence of this disorder in a pair of sibs originally considered affected by Ohdo syndrome, and then re-evaluated as YSS, following the discovery of thyroid anomalies (Family 6) [Verloes et al., 2006]. By comparing the clinical features of the three YSS patients presenting with a possible autosomal recessive pattern of inheritance with the present siblings, we found that they share facial features, and have mental retardation and thyroid abnormalities [Bonthron et al., 1993; Verloes et al., 2006]. Differently from our patients, none of these cases had microcephaly, while they displayed heart defects (3/3), seizures (2/3), and splenomegaly (2/3). Based on these findings we favor to tabulate separately the present siblings from the known YSS subjects, although they are likely falling within this heterogeneous spectrum (Table I).
In conclusion, the present patients display a distinct constellation of craniofacial features, including microcephaly, blepharophimosis, telecanthus, and upward slanted palpebral fissures, in association with severe poor weight gain, developmental delay, absent speech, and variable MCA. Several characteristics are superimposing those of BMRSs, with many findings overlapping the YSS subtype. The recent discovery of different chromosome imbalances establishes that the so-called YSS is to consider more a heterogeneous phenotype rather than a clinically recognized disorder in which only few patients reported support a monogenic autosomal recessive inheritance. Some unique clinical characteristics and familial recurrence in our sibs, born from unaffected parents, suggest that they may represent a clinical and genetic variant within the BMR–YSS subtype.
Clinical information and images of the two sibs were uploaded to the web-based Dysmorphology Diagnostic System (DDS) developed by DYSCERNE—A European Network of Centres of Expertise for Dysmorphology. These patients were discussed with the DDS expert panel which concluded that they likely represent a previously undescribed variant of multiple congenital anomaly-autosomal recessive syndrome. This study was supported by grants from Italian Ministry of Health (Ricerca Corrente 2010) and DYSCERNE—A European Network of Centres of Expertise for Dysmorphology, funded by the European Commission Executive Agency for Health and Consumers (DG Sanco), Project 2006122. We are grateful to the patients and their family. We thank Prof. Raoul Hennekam for his substantial help in revising this paper.