Marshall-Smith syndrome: case report of a newborn male and review of the literature

Abstract

Marshall–Smith syndrome is a rare congenital condition, characterized by advanced bone age, facial anomalies and relative failure to thrive. We report a newborn male with Marshall–Smith syndrome and summarize 21 previously reported cases. We report cerebellar hypoplasia in our patient, which has not been previously reported in subjects with this rare syndrome. This patient’s findings broaden the phenotypic spectrum seen in Marshall–Smith syndrome.

CASE REPORT

A 3060 g white male infant was born to a G4 P2 Ab2, 36-year-old Caucasian mother. Prenatal ultrasound revealed bilateral hydronephrosis, polyhydramnios and choroid plexus cysts. Terbutaline was required to halt preterm labor, at 32 weeks gestation. Labor was induced at 39 weeks, and the patient was born vaginally in vertex position. Multiple congenital anomalies and intermittent airway obstruction were noted at birth. Dysmorphic features identified included micrognathia; a prominent forehead; shallow orbits with ocular proptosis; a flat nasal bridge; a small, upturned nose with wide, anteverted nares; left choanal atresia; arachnodactyly; mild hypertrichosis; and hypotonia (see Figure 1). No family members displayed similar features, and the parents were nonconsanguinous. He was discharged after 6 days.

FIGURE 1.

Frontal and profile view of our patient with Marshall–Smith syndrome at 4 weeks of age

Following 3 weeks of care at home, the patient was admitted to the hospital with severe failure to thrive and poor weight gain secondary to poor oral intake (admit weight was 2790 g). A barium swallow and upper GI series revealed abnormal esophageal motility and probable gastroparesis; subsequent barium swallow studies showed improvement after treatment with cisapride. Because of persistent hypotonia and dysmorphic features, an MRI of the brain was obtained and demonstrated a hypoplastic cerebellum with an enlarged cisterna magna. Following repeated episodes of low oxygen saturation due to choanal atresia and upper airway obstruction, he was placed on supplemental oxygen. An X-ray of the chest to rule-out aspiration pneumonia revealed split-type epiphyses in both humeri and sacral abnormalities. A follow-up skeletal survey was significant for an estimated bone age of 3 to 4 years in the wrists, elbows and femoral epiphyses. Hand X-rays demonstrated broadening of the proximal and middle phalanges of the second through fourth digits as well as advanced skeletal maturation (see Figure 2). A voiding cystogram showed grade III vesicoureteral reflux on the left side. Chromosome studies revealed a normal 46, XY karyotype.

FIGURE 2.

Hand and foot X-ray findings showing advanced bone maturation.

Genetic evaluation was requested when the patient was 1 month of age. At that time, the patient weighed 3025 g (5th percentile), was 58 cm long (95th percentile) and had a head circumference of 37 cm (50th percentile). Eye and hearing evaluations were normal. Echocardiography and electrocardiogram were both normal. Normal blood chemistry and a normal hemogram were found. Prior to discharge from the hospital, a tracheostomy was performed to lessen the patient’s persistent oxygen desaturations, and a G-tube was placed simultaneously due to his failure to thrive.

DISCUSSION

Marshall–Smith syndrome (MSS), as first described in 1971 (Marshall et al., 1971) is a rare congenital condition, characterized by advanced bone age, facial anomalies and relative failure to thrive. Table 1 summarizes information from 21 previously reported cases (Chatel et al., 1998), compared with the findings of our proband. In addition to his accelerated skeletal maturation, our patient demonstrated several features typical for MSS, including a small face with a prominent forehead and eyes, micrognathia, anteverted nares, choanal atresia and hypertrichosis. His normal karyotype is also consistent with previous cases of MSS (Tipton et al., 1973; Hassan et al., 1976; Johnson et al., 1983; Roodhooft et al., 1988; Yoder et al., 1988; Charon et al., 1990; Eich et al., 1991; Sperli et al., 1993; Sharma et al., 1994; Williams et al., 1997; Chatel et al., 1998). Our patient had hydronephrosis, which has been associated previously with MSS (Hassan et al., 1976). Charon et al. (1990) reported polyhydramnios and preterm labor in a patient with MSS; this complication was also present in our patient.

TABLE 1.

Summary of reported features in Marshall-Smith syndrome

Trait	Proband	Literature	%
Musculoskeletal
Advanced bone age	+	21/21	100
Broad phalanges	+	20/20	100
CNS/Neurological
Neurodevelopmental abnormalities	+	15/16	94
Structural brain anomalies (excluding cerebellar hypoplasia)	−	9/17	53
Cerebellar hypoplasia	+	0/21	5
Craniofacial
Flat nasal bridge	+	20/21	95
Anteverted nares	+	17/18	95
Prominent eyes	+	19/21	91
Prominent forehead	+	18/21	86
Micrognathia	+	17/21	82
Small face	+	15/21	73
Blue sclera	−	11/21	50
Glossoptosis	−	6/20	29
Choanal atresia/stenosis	+	3/20	19
Other
Normal karyotype	+	15/15	100
Failure to thrive	+	13/16	82
Hypertrichosis	+	10/21	50
Umbilical hernia	−	8/20	38

Adapted from Chatel et al. (1998).

Structural brain anomalies are often associated with MSS (Chatel et al., 1998). These include macrogyria (Tipton et al., 1973); agenesis of the corpus callosum (Pappas and Rekate, 1991; Sperli et al., 1993); optic atrophy (Sperli et al., 1993); cerebral atrophy (Pappas and Rekate, 1991); polymicrogyria (Yoder et al., 1988); and pachygyria (Flatz and Natzschka, 1978). However, no previous patients have been reported with cerebellar hypoplasia. We feel this finding in our patient represents an additional feature in the phenotypic spectrum of MSS.

Long-term survival is a problem in MSS patients (Marshall et al., 1971; Tipton et al., 1973; Flatz and Natzschka, 1978; Hassan et al., 1976; Johnson et al., 1983; Chatel et al., 1998; Yoder et al., 1988; Eich et al., 1991; Sharma et al., 1994; Cullen et al., 1997). However, early infancy mortality does not appear to be an inevitability. For example, Roodhooft et al. (1988) reported a patient with MSS diagnosed at four years of age. Williams et al. (1997) also summarized four additional cases of MSS surviving well past infancy. The oldest documented patient with MSS was a 15-year-old with an unrelated cloacogenic polyp (Washington et al., 1993). A review of the literature indicates that a lack of severe respiratory complications appears to be an indicator for survival past infancy (Sperli et al., 1993). We would encourage the reporting of additional patients to further the phenotypic spectrum and to determine the natural history and prognosis of those patients with this rare disorder.