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Article Summary and Review
by Ned Rapp MD
The Adult Phenotype in Costello Syndrome
Susam M White, J. M Graham Jr, B. Kerr, K. Gripp, R. Weksberg, C. Crystrynbaum, J. L Reeder,F. J Stewart,M. Edwards, M. Wilson and A. Bankier
American Journal of Medical Genetics 136A:128-135(2005)
Introduction and Reviewers Remarks
Costello syndrome has been reported in 200 patients (Gripp-2005) but it is thought that this figure represents an underestimate, particularly in adults (see Cassidy and Allanson’s “Management of Genetic Syndromes”: Wiley-Liss, 2005). It is characterized by moderate intellectual disability, short stature and facial dysmorphology that is usually but not always unique. The facial dysmorphology in adults with this syndrome includes: full lips, a large mouth, a broad forehead, curly or sparse fine hair, progressive facial coarseness in adulthood and a broad nose with a wide nasal bridge (Fig 1). Musculoskeletal features include joint laxity, ulnar deviation of the wrists and fingers and the fingers are also splayed. The Achilles tendons are tight. Cardiovascular features that occur frequently include supraventricular tachycardia which may be multifocal or chaotic. Hypertrophic cardiomyopathy and pulmonic stenosis also occur, as well as other congenital cardiac lesions. Malignant tumors occur in 15% of patients with Costello syndrome at some point during their lifetime. Children often develop rhabdomyosarcoma or neuroblastoma. Papillomata (particularly of the nares and perianal area) occur also. Both benign and malignant tumors occurred in the group of patients in this paper. The benign tumors were described as multiple ductal papillomatas in two women and a choroid plexus papillomata in the fourth ventricle in a man. Endocrine problems in this group included central hypogonadism, osteoporosis, and delayed puberty. Four patients had had adult onset gastroesophogeal reflux, of which three had chiari type I malformations (protrusion of the cerebellum into the spinal canal). Fourteen patients had mild to moderate intellectual disabilities. Two patients developed carcinoma of the bladder (in one case at age 16 and a second case at age 25). A relatively large percentage of patients had hypertrophic cardiomyopathy, a frequent cause of death in adolescents and young adults with other syndromes and a rare cause of death in young athletes.
Summary of Article
The patients were recruited through the International Costello Syndrome Support Group. A questionnaire was completed by all of the participants and all of them were seen by a geneticist.
Results and Discussion
In addition to the features described in the introduction, two of the females in this article had marked fronto- temporal balding (see figure 2). In addition, there is redundant loose skin over joints and in the hands and feet. As mentioned before, there is a noticeable increase in facial coarseness as the patient ages. Hyperkeratosis of the hands and feet with excessive sweating was a problem in several patients. In the case of several patients, excision of excess plantar skin was noted in several patients.
Height and Growth
The mean height was 137cm for females and 142cm for males. Adult height was reached at a mean age of 21 years for the entire group (range 16-28 years). Three female patients (patients 4,7 and 10) had heights of 151, 154 and 127cm (compared to the average female height of 130 cm in the group). Patient 4 had been given growth hormone for documented growth hormone deficiency from age 3 to 15 years, but the growth hormone was discontinued at age 15 because of the development of cardiomyopathy. Patient 7 had been given growth hormone from age 5 to 9 and an echocardiogram showed no cardiomyopathy after the growth hormone was DC’d. Growth hormone deficiency was not documented in this case and it was simply given because the patient was short. Patient 10 was given growth hormone from age 6 to 14 but growth hormone deficiency was not documented (she had apparently was given growth hormone because of ”hypoglycemic seizures”.)
Posture and Mobility
The standing posture was stooped with flexed elbows and wrists and the hands held in ulnar deviation (see figure 3). The gait was widespread in all patients. Joint contractures were present and scoliosis remained static after adolescence (all patients had contractures and scoliosis). Six patients were ambulatory for short distances. The reasons for their inability to ambulate normally were as follows: 1) Three patients had Chiari type 1 malformation with resultant weakness, 2) One patient had fatigue probably related to a prosthesis for rhabdomyosarcoma, 3) Two patients were too fatigued to walk longer distances. One patient never walked because of a severe intellectual disability. The remainder of the patients were ambulatory.
Six of the eight females in the report had delayed puberty and two had primary amenorrhea. It was of interest that one of the two patients who had primary amenorrhea had a normal ultrasound with FSH,LH in the low adult range, and estrogen levels in the adult range which, of course, results in a high level of estrogen that is not modulated by feedback from the pituitary via FSH and LH levels. This raised the possibility of chronic high estrogen and its side effects and she was placed on contraceptive therapy. The second patient with amenorrhea had low estrogen and normal menstrual periods which raised the possibility of the long term effects of low estrogen.
Five of the nine males had delayed puberty but details were not discussed.
Eight patients (five females and three males) had abnormal DEXA scans. Five were diagnosed with osteoporosis and three with osteopenia.
As mentioned previously, patient 16 had been previously reported with rhabdomyosarcoma of the right foot. Patient 8 and patient 10 both had transitional carcinoma of the bladder. Patient 10 was 16 at the time of diagnosis. Patient 8 presented (at age 25) with microscopic hematuria and an ultrasound sound showed an 8mm mass in the bladder (histologically confirmed as transitional cell carcinoma of the bladder). (Reviewer’s note: carcinoma of the bladder usually presents with gross hematuria but the entire panoply of urinary symptoms may result from bladder carcinoma).
The benign tumors in this series included two intra-ductal papillomatain two females and a choroid plexus papillomata in the fourth ventricle. Other series have included severe breast fibro-adenomas, a vestibular schwannoma at 33 years and parathyroid adenoma at 23 years.
Eleven patients had neuro-imaging studies, four had an MRI and 7 had a CT scan. Findings in this group of patients included the following: Chiari type 1 was identified in patient 1 at age 27 after she developed frontal headache, upper limb weakness and an unsteady gait, scoliosis and lower limb hypereflexia. She had been diagnosed at age 16 (she became part of the study at age 27). The cervicomedullary junction was situated at the C2-C-3 level with moderate descent of the cerebellar tonsils. Patient 8 had a Chiari type 1 malformation identified at age 29 on an MRI at age 29. It was performed to investigate a high serum prolactin level. He had headaches, upper limb weakness choking episodes and gastroesophogeal reflux. As far as the prolactinemia, there was no galactorrhea, and the pituitary appeared normal on MRI scan. The patient had a lesion in the forth ventricle that was thought to be a choroid plexus papilloma and did not change in appearance over four months.
Gastroesophogeal reflux was present in four patients in this study, three of whom had a chiari malformation. Because of this fact, the authors suggest that consideration be given to obtaining an MRI in adults with Costello syndrome who develop gastroesophogeal reflux.
Intellectual Disability and Behavior
Fourteen of the patients had mild or moderate intellectual disability and three had severe intellectual disability.
The principal features of Costello syndrome in adults include: mild or moderate intellectual disability, unique facial dysmorphology, short stature, the predisposition to bladder carcinoma and benign tumors (specifically, intraductal papillomata of the breast), the possibility of Chiari syndrome, and endocrine abnormalities including delayed puberty and primary amenorrhea, osteoporosis and gastroesophogeal reflux
The best way to commit the facial dysmorphology of a genetic syndrome to memory, in the author’s opinion, is to look at a group of pictures of patients with the syndrome of different ages and determine what features stand out in most of them. In my opinion, the most prominent dysmorphic features of Costello syndrome that can help differentiate it from Noonan or Cardio-facial-cutaneous syndrome include: large mouth, large lips, and a large nose which I would call “splayed”. Other minor features would include fine hair and cupped ears.
Other features which will aid in the differential diagnosis include: 1) pulmonic stenosis, which is seen in all three syndromes but is more common in Noonan syndrome, 2)atrial tachycardia which is seen in all three conditions but is more severe in Costello syndrome, and 3) chaotic atrial tachycardia which is unique to Costello syndrome. Additionally, the frequency of hypertrophic cardiomyopathy is 30% in Costello syndrome, 20% in Noonan syndrome, and 10% in Cardio-facial-cutaneous syndrome.
All three syndromes are associated with tumors in some cases, aside from the ones mentioned that are associated with Costello Syndrome (myelomonocytic leukemia in Noonan syndrome, acute lymphoblastic leukemia and hepatoblastoma in Cardio-facio-cutaneous syndrome). The studies obtained for the diagnosis of Costello syndrome is not mentioned in this paper but the diagnosis should only be considered in those individuals who are positive for the HRAS gene (which is part of the RAS/mitogen/MAPK surveillance system). This gene predisposes the patient to malignancy in Costello syndrome.
1) A 20 year old male is seen in the outpatient clinic stating that he has been diagnosed with Costello syndrome. He is accompanied by his mother who says that he has had trouble swallowing for the past several weeks and he has complained of a burning sensation in his throat and reflux of undigested food. In addition, his gait has become unsteady, and his arms appear weaker when he lifts things. Physical exam reveals a decreased gag reflex, ataxia, increased deep tendon reflexes and slight weakness of the extremities. You should (as a first step):
a) Obtain a swallowing study
b) Order an MRI of his brain
c) Measure his acid output with a Bravo capsule or NG tube
2) A 21 year-old patient with Costello syndrome is seen whose chief complaint is fatigue, a feeling that he is going to pass out, and shortness of breath. On physical exam he is found to have a fourth heart sound and a diamond shaped systolic cardiac murmur best heard at the lower left sternal border and at the apex. The murmur heard at the apex is holosystolic and blowing in quality. The electrocardiogram shows ST segment and T wave abnormalities, abnormal q waves and left ventricular hypertrophy. The chest x-ray shows an enlarged cardiac silhouette. The most likely diagnosis is:
a) Coronary artery disease
b) Dilated cardiomyopathy
c) Hypertrophic cardiomyopathy
3) In this paper not much detailed information is given about investigations related to the cause of abnormalities in pubertal development in regard to the usual physiological events that cause puberty, except to say that some abnormality in the hypothalamic-pituitary axis (which they refer to as central hypogonadism) exists. One patient with amenorrhea had FSH, LH in the low adult range and estradiol levels in the normal adult range and a normal pelvic ultrasound and was placed on birth control pills to eliminate the possibility of chronically high estrogen. The second patient had normal menstrual cycles with low estrogen. This explanation is unclear and it would be wise to eliminate other causes of abnormal puberty. Which of the following can cause abnormalities in menstruation, menarche or puberty:
a) A craniopharyngioma
b) Polycystic ovary disease
c) Chronic, recurrent Chrohn’s disease
d) Hypothalamic factors(diet, exercise, etc)
e) Ovarian failure
f) A wide variety of genetic conditions
g) Pituitary lesions
h) Cervical stenosis and other pelvic anatomic abnormalities
i) All of the above
4) The arrhythmia depicted below occurs most frequently in which of the following:
a) Noonan’s syndrome
b) Costello syndrome
c) It is not typical of either syndrome
5) An 18 yo male who has been diagnosed with Costello syndrome is found to have a positive hemoccult test on a urine strip at the time of his yearly physical exam by his private physician. Microscopic exam of the urine reveals red cells and occasional casts. This patient has mild intellectual disability and has just finished competing in the state finals of the Special Olympics the day before. Under these circumstances , you would:
a) First refer him to a urologist for cystoscopy because of the predisposition of patients with Costello syndrome to transitional cell carcinoma of the bladder.
b) Perform an ultra sound of the kidneys
c) Refer him to a renologist for possible kidney biopsy to rule out nephritis
d) Have him rest for three days and repeat the urinanalysis
1) B: Order an MRI of his Brain.
Patients with Costello syndrome have an increased incidence of Type 1 Chiari syndrome (see page 248 in Schwaiman and Ashwals Pediatric Neurology, Principles and Practice. Mosby, St. Louis, 1999). This can result in herniation of the cerebellum through the skull resulting in ataxia results. The resultant compression of the brain at the level of the medulla and the spinal cord, which may involve cranial nerves IX-XII, may cause difficulty in swallowing and a decrease in the gag reflex, and may also compromise drainage of spinal fluid (often accompanied by hydrocephalus). Additionally,this may cause weakness of the extremities, resulting in increased deep tendon reflexes. This patient may have hydrocephalus which frequently accompanies Chiari type I, but this is unlikely since he did not complain of headaches.
2) C: Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy is the most common cardiac lesion in Costello syndrome. The “blowing” murmur at the apex probably represents mitral regurgitation associated with this type of cardiomyopathy.
3) I: All of the above
Under normal circumstanced, development of secondary sexual characteristics begins in females at an average age of 11.2 and 12.8 with regard to breast bud development and menarche, respectively. The standard deviation of these events is approximately one year depending on nutrition, geography and many other variables. Girls who have not reached menarche by age 16 should be investigated further. Genetic syndromes such as Costello syndrome often delay the beginning of puberty and menarche, though one should not assume that this is always the case. The usual progression of events is the secretion of trophic hormones by the hypothalamus, followed by the secretion of FSH and LH by the pituitary, followed by the secretion of estrogen by the ovary which exerts a feedback effect on the pituitary secretion of FSH and LH.
4) B: Wolf Parkinson White Syndrome
The EKG in question shows the Wolf-Parkinson-White arrythmia that is not typical of a or b and occurs in the general population.
5) D: Have him rest for three days and repeat the urinalysis
The most common symptom of carcinoma of the bladder is moderately gross to gross hematuria. However, burning, frequency and flank pain can occur as well. The urinalysis does not show casts in most cases. This patient does not have dysuria and is seen after he has been exercising vigorously. He has casts as well as erythrocytes, but after three days of complete rest, his urine is clear microscopically. This scenario is typical of exercise induced microscopic hematuria. His urine would not be clear after three days of rest in either nephritis or carcinoma of the bladder.
Pictures of Patients with Costello Syndrome