Case report

Clinical profile of a male with Rett syndrome

Sarojini S. Buddena,*, Heather C. Dorseyb, Robert D. Steinerc

aDepartment of Pediatrics, Child Development and Rehabilitation Center, Doernbecher Children’s Hospital,

Oregon Health and Science University, CDRC 707 SW Gaines Road. Portland, Oregon 97239, USAbDepartment of Obstetrics-Gynecology, Center for Women’s Health, Doernbecher Children’s Hospital,

Oregon Health and Science University, CDRC 707 SW Gaines Road. Portland, Oregon 97239, USAcDepartments of Pediatrics and Molecular and Medical Genetics. Child Development and Rehabilitation Center, Doernbecher Children’s Hospital,

Oregon Health and Science University, CDRC 707 SW Gaines Road. Portland, Oregon 97239, USA

Received 2 August 2004; received in revised form 13 November 2004; accepted 7 March 2005

Abstract

We describe a clinical profile of a male with Rett syndrome who presented initially with significant axial and peripheral hypotonia, head

and truncal titubation and global delay. He is non-ambulatory, lost the few words he had learned and gradually developed hand stereotypes,

breathing difficulties, seizures, scoliosis and has osteoporosis sleep problems and sludging in his gall bladder. Prior to diagnosis he underwent

comprehensive neurological, metabolic and genetic investigations. After his older sister was diagnosed with atypical Rett syndrome; MECP2

mutation studies on him revealed a pathogenic mutation. His mother is a Rett carrier with a skewed inactivation of chromosome X. Clinical

signs and symptoms required to meet the criteria for diagnosis of Rett syndrome have gradually evolved over time. This case demonstrates an

unusual family history for Rett syndrome and alerts readers to the utility of screening males for Rett syndrome.

q 2005 Elsevier B.V. All rights reserved.

Keywords: Male; MECP2 mutation; Recurrent Rett syndrome; Autism; Gall bladder; Osteoporosis

1. Introduction

Rett syndrome is an X-linked dominant condition that

occurs predominantly in females [1]. It was formerly

presumed to be lethal in the hemizygous state accounting

for the relative lack of reported affected males. Clinical

characteristics have been well documented in females with

classic Rett syndrome who have MECP2 mutations.

Currently there are very few reported males with

MECP2 mutations ranging in severity from early neonatal

encephalopathy [2] to young adults with mental retar-

dation and neurological signs [3]. Clinical characteristics

and criteria have been well described for females with Rett

Syndrome to assist in the diagnosis [4], however, there is a

paucity of this information for males with MECP2

mutations.

0387-7604/$ - see front matter q 2005 Elsevier B.V. All rights reserved.

doi:10.1016/j.braindev.2005.03.018

* Corresponding author. Fax: C1 503 494 4447.

E-mail address: sbudden@comcast.net (S.S. Budden).

2. Case report

This boy is the second child born to a 30 year old mother.

Alpha-feto-protein screen was abnormal but karyotype was

46, XY. Delivery was at term and uncomplicated. Birth

length was 51 cm (50%) birth weight was 3.6 kg (50%) and

head circumference 34 cm (25%). Family reported normal

early development for the first 6 months, however, review of

home videos revealed an alert child who was hypotonic. He

nursed for 6 months but was described as having a weak

suck and was quiet and ‘mellow’. He rolled at 4 months and

sat unsteadily at 8 months. He commando crawled at 10

months. Following this period he made no progress and was

referred at 15 months to the developmental clinic for poor

weight gain, hypotonia and truncal unsteadiness. Parents

reported that he had never made attempts at four-point

kneeling or coordinated crawling. At 9 months he had been

able to clap his hands but was not doing this when evaluated

although he would reach for toys and bring them to his

mouth. He had not acquired a pincer grasp. He did have a

few vocalizations but no specific words. If held he could

bear weight but was unable to pull to sit or stand.

Brain & Development 27 (2005) S69–S71

www.elsevier.com/locate/braindev

S.S. Budden et al. / Brain & Development 27 (2005) S69–S71S70

Comprehensive neurological, metabolic and genetic inves-

tigations were non-diagnostic.

At 18 months his left eye was turning in, he had more

drooling and feeding problems with symptoms of gastro-

esophageal reflux. He had central hypotonia with brisk deep

tendon reflexes, clonus, a planter flexor response on the

Babinski, axial and peripheral ataxia. By 2 years and 6

months he was much more tremulous and showed growth

failure with deceleration of head circumference. His grasp

was random and uncoordinated. He spoke an occasional

phrase and he had made no progress in his gross motor

development. He was referred to the neurometabolic clinic

and had additional extensive diagnostic investigations

including a repeat MRI, EEG, urine and blood studies for

genetic metabolic and progressive neurological conditions

such as Pelizaeus-Merzbacher, Ataxia telengectasia, Frie-

dreich’s ataxia, Spino-cerebellar ataxia, leukodystrophies,

peroxisomal and mitochondrial disorders. Repeat genetic

studies ruled out Fragile X, Angelman’s and Prader-Willi

syndromes.

At 5 years of age he started having seizures and had

epileptiform activity on EEG. He takes anticonvulsants. Six

months later he fractured his left femur, which healed.

Osteoporosis was diagnosed and confirmed by DEXA. He

developed mild ptosis of the right eye; his breathing pattern

changed and he lost his ability to use his hands consistently,

with onset of hand stereotypes, such as bringing hands

together in midline. He developed increasing rigidity of his

Fig. 1. Photo of 6 year old male with Rett syndrome.

lower extremities and some rigidity of his arms. Sleep and

constipation became major problems. [Fig. 1]

This boy’s older sister had developed normally until 25

months of age. She was then reported to have speech and

language delays and ataxia, but ambulated freely and paced

frequently. She used stairs, was able to use her hands to self-

feed, scribble, and manipulated toys and puzzles. She had

developmental issues and had been diagnosed with autism.

She had been investigated with her brother and all studies

were normal. By parental report she started having hand

stereotypes at 8 years, although home videos showed subtle

hand abnormalities to be present by age 3 years. She was

referred for diagnosis of possible Rett syndrome. Her

MECP2 mutation studies were positive for the S134C

mutation. Her mother’s and brother’s studies were

subsequently positive for the same mutation. The mother’s

parents were tested and were negative suggesting that

mother represents the de-novo mutation within the family

She is a college graduate but reported having had difficulty

with speed and dexterity. Her mild clinical course is likely

attributed to her skewed X-inactivation favoring the normal

X chromosome in 98% of her cells.

By age 10 years our patient had developed scoliosis

following subluxation of his left hip which was surgically

corrected. His seizures persist, and feeding has become a

major problem requiring the use of a gastrostomy. Due to

abdominal discomfort he had an abdominal ultra sound

which revealed an enlarged gall bladder with sludging

of bile.

3. Discussion

Rett syndrome has a more variable clinical course than

previously recognized [5]. Identification of the MECP2

mutations allows diagnostic confirmation in approximately

70–80% of clinically suspected cases [6]. Recognition of

Rett syndrome in males has been based on their clinical

profile. Since there have been few reports of Rett males

confirmed by mutation analysis the spectrum of clinical

symptoms is not fully known. There have been fewer

families with a mother who carries a Rett mutation and who

has an affected son and daughter.

The first report in 1990 [3] described two males in their

thirties with some of the features of RS but the genetic

confirmation was not possible then. Another report

postulated that two males with neonatal encephalopathies

in families with Rett syndrome possibly carried the locus on

the X chromosome [2]. In 1999 another male patient was

described who met all the supportive criteria for RS but

without the genetic confirmation [7]. A three generational

family with RS is reported with two affected males with

severe mental retardation and progressive spasticity [8].

More recent descriptions of MECP2 mutations in males

with RS and clinical information have provided additional

information on the Rett phenotype in males. [9,10].

S.S. Budden et al. / Brain & Development 27 (2005) S69–S71 S71

The finding of a MECP2 mutation in the sister of this boy

who carried the diagnosis of autism led to testing him and

his mother. This raises the importance of thorough

neurological assessment of females with autism to differ-

entiate atypical or milder forms of RS from autism spectrum

disorders. The S134C mutation is a missense mutation

and occurs in the methyl-cytosine binding domain of the

MECP-2 gene. Mutations in this region are thought to

interfere with MECP-2s ability to bind to methylated CpGs.

Review of the literature identified four reported cases of

S134C mutation [11–14]. They all occurred as de novo

mutations in females described as having classic Rett

Syndrome. Additional cases are reported in the RettBase

data base (http://mecp2.chw.edu.au), however clinical

information regarding severity of the condition is not

available. It is unclear why the sister in this family shows a

milder atypical course than those previously described in the

literature. She did not show skewed X-inactivation, so the

likely explanation is some unidentified genetic influence.

The brother who is more severely affected developed all the

necessary diagnostic criteria for Rett syndrome.

4. Conclusions

We stress the usefulness of testing for MECP2 mutations

in males with unspecified mental retardation and severe

progressive neurological problems. Perhaps this will soon

become a more widespread screening test as has the study

for Fragile X Syndrome. We also suggest need for a

neurological assessment of all girls with autism and careful

consideration for testing for MECP2 mutations analysis.

Acknowledgements

We would like to thank the family for their patience and

cooperation and members of the Metabolic clinic at OHSU

who provided support services. We would like to acknowl-

edge Michael Friez, Molecular Diagnostic Laboratory,

Greenwood Genetic Center, Greenwood, SC, for doing the

mutation studies.

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