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The Natural History of Aging in Cornelia de Lange Syndrome

in Ned Rapp MD, Articles

Article Summary:

The Natural History of Aging in Cornelia de Lange Syndrome
Article Reviewed and Summarized By Ned Rapp, MD

Original Article Citation: Am. J of Med. Genetics Part C (Seminars in Medical Genetics) 145C:248–260 (2007)

Authors: Antonie D. Kline, Marco Grados, Paul Sponseller, Howard P Levy, Natalie Blagowidow, Christianne Schoeder, John Rampola, Douglas K Clemens, Ian Krantz, Amy Kimball, Carmen Pichard, David Tuchman

Reviewers comments: Cornelia de Lange syndrome is a rare syndrome characterized by small stature, learning disabilities or intellectual disabilities, absence of forearm(s) and very distinctive craniofacial abnormalities such as high arched eyebrows, synophrys(eye brows crossing the nasal bridge), downslanting palpebral fissures, and downturned corners of the mouth. Most of the descriptions involve children. The purpose of this article was to describe the facial features and other clinical characteristics seen in adolescents and adults.

In the process of describing the natural history of Cornelia de Lange as it changes throughout adulthood, changes in facial morphology are described in some detail.  This article includes photographs of patients at different ages (see figures 1,2,3.) The variety of clinical characteristics of patients with this syndrome continues with age. For example, some develop pronounced sagging and wrinkling of the skin with age, but the age at which they develop these characteristics obviously varies. Thus far, two genes (NIPBL on chromosome 5 and SMCIA on the X chromosome) have been found which are associated with the disease, (but at this point the role of these genes has not been established - see section on molecular diagnosis).   This pattern is most consistent with autosomal dominant inheritance with germ line mosaicism. (Russell et. al. 2001; Am J of Med Genet. 104: 267—276.)

This study was derived from a clinic that is described as a multidisciplinary genetics clinic for adolescents and adults. The minimum age was 17. Clinical characteristics of the group were described and recommendations for follow care up were given as well. There were 49 patients in the study.

Clinical Characteristics

A.  Facial Dysmorphology
Features, which are considered typical, include semicircular eyebrows with synophrys, a long smooth philtrum, long and curly eyelashes and downturned corners of the mouth, producing a crescent shaped mouth. Many have anteverted nares; a depressed nasal bridge and the majority are microcephalic.

Figure 1 shows a progression of changes in facial morphology as the patient ages. One patient’s facial appearance may change in a different way and at a different age than another patient, so that pictures of patients in childhood demonstrating more “typical” features may be important. The down slanting palpebral fissures remain, as do the high arched eyebrows in the vast majority. In Patient 9, high arched eyebrows are shown as well, as is a high smooth philtrum (the part of the face between the base of the nose and the upper lip) and a thin upper lip which is seen in some patients, while patient  J shows down slanting palpebral  fissures and a synophrys, and  patient I has bilateral anteverted  nares, a depressed nasal bridge, thick curly eyelashes, downturned corners of thin lips producing a crescent shaped mouth,  semicircular eyebrows ,and  a long, smooth philtrum (and bilateral amputations).

In patients A-J, the adolescent and adult patients have more typical features than in patients K-R, who have lost some of their childhood “typical” features.  Many of the older patients are quiet and retiring, particularly those who have mild intellectual disability (see the section on neurological manifestations) and the face may appear very different as the patient ages –with sagging of facial tissue and elongation of the nose as well as elongation of the face (see patient R.) Therefore the general physician may be presented with an undiagnosed adult patient who appears to be mildly intellectually disabled who is short and has sagging of the facial tissue and a long nose and face and the diagnosis has never been made.

The synophrys become bushier with age in most.  The anteverted nares and short nose were present in 78%(a “typical” feature) while, the jaw was square in 45% which tends to occur in “older” patient -see patent R). Sixty-five percent had down turned corners of the mouth. Some of the patients appeared older than their chronological age. Patient R is a good example of a person who appears older than his chronological age (which is 50)(.Since these patients are small, the illustrations may cause them to look younger-reviewers comment). The authors’ major point (in the reviewer’s opinion) is that some adults with Cornelia de Lange may not have as large a panoply of typical symptoms as most children do, although the authors don’t provide symptomatic data from studies of children. However, because of some of the other symptoms associated with Cornelia de Lange syndrome, particularly the large number of cardiac manifestations, an accurate diagnosis is important, therefore, this is an important article

B.  Gastrointestinal Manifestations
Eighty-two percent had GI reflux symptoms and 75% had their reflux confirmed by gastrointestinal studies that showed esophagitis in 35%, gastritis in 22%, duodenitis in 13%, esophageal strictures in 12% and hiatal hernia in 19%. Biopsy of the esophagus revealed metaplasia in 9%. Barrett’s esophagus was detected in 10%(the age range was 19-30 years for Barrett’s esophagus).

C. Genitourinary Manifestations
Eighty-two percent had a history of cryptorchidism- (only one of the groups had not had surgical correction)

D. Cardiovascular Manifestations
Congenital heart disease occurred in 22%. Four had a ventricular septal defect, two had an atrial septal defect (one of which had pulmonary stenosis as well), four had pulmonary stenosis, one had mitral stenosis and one patient had tetrology of fallot. Hypertension was found in 8%. Of this last group, one patient had nephrotic syndrome and pericardial effusion of unknown etiology, one had a pericardial effusion and congestive heart failure with mitral and aortic insufficiency, and two had idiopathic hypertension (one of these two also had a pericardial effusion).

E. Otolaryngologic and Dental Manifestations  (See Figure 2)
1) Cleft palate in 37%
2) Submucous palate in 14%
3) Chronic sinusitis in 34%
4) Nasal polyps in 12%
5) Most patients had dental crowding and delayed secondary tooth eruption

F. Ophthalmic Manifestations
1) 41% had ptosis
2) 50% had high myopia

G. Musculoskeletal Manifestations
1) Absent forearms in 16%-usually bilateral
2) Absent digits in 9%
3) Polydactyly in 6% (See Figure 3)
4) Proximately placed thumb in 20%
5) Scoliosis in 39%
6) Low bone density in 86% of 14 patients who had a DEXA bone scans

H. Skin Manifestation
1) Hypertrichosis in 80% (See Figure 4)
2) Cutis maramata (or reticulated pattern of vessels) in 61%

I. Endocrine Manifestations
1) Delay in onset of puberty until age 15 (males) and age 13 (females)
2) Lack of axillary hair in 33% of males and females
3) Ninety percent of males and females had pubic hair

J. Neurologic Manifestations
1) The majority of patients had increased ankle reflexes
2) Twenty-five percent of patients developed seizures-usually during adolescence
3) Severe intellectual disability in 43%, moderate to severe intellectual disability in 8%, moderate ID in 16%, mild- moderate ID in 8%, mild ID in 16%, borderline intelligence in 6%, normal intelligence with learning disabilities in 3%. Those with milder ID tended to be quieter in demeanor.

K. Behavioral Manifestations
1) Self-injury in 59%, aggression in 37%, ADHD in 20%, (all of these individuals had absent speech)
2) Anxiety was present in 33%, and depression in 11%
3) Forty percent had autistic behavior
4) Forty percent had quiet, retiring behavior

L. Molecular Testing
NIPBL (on chromosome 5) and SMCIA gene (on the X chromosome) determinations were obtained in 53% of the patients. Ninety-three percent of this group had mutations in the NIPBL gene and 7% had mutations in the SMCIA gene. In a study by Jackson et al. (Am J of Medical Genetics 1993; 47:940-946) of siblings with the disease. It was concluded that the risk to siblings of probands was 1.5% when parents had no stigmata of the disease, which implicated germ line mosaicism as the source of the mutation. (This article had no parental data, but the great majority of patients have parents who do not have findings consistent with the disease, but the NIPBL and SMC1A gene can be partially confirmatory in all patients suspected of having the disease and recently a paper demonstrated that if the affected individual is positive for NIPBL, the chance of having another child having the disease rises to 50%(Deardorf et al, Gene Reviews, 9/16/2005)

M. Summary
1) Many of these patients live into their fifties-a radical change from previous thinking.
2) Congenital heart disease is often still present in some of these patients in adulthood - it is typically stable but an ECHO should be obtained if the patient has never had one.
3) There is a delay in secondary tooth eruption so dental visits should occur every 6 months.
4) Sinusitis and nasal polyps may be present so ENT consultation is recommended if there is still a suspicion.
5) GERD is common, so symptoms suggesting it should be pursued with a Bravo capsule (a capsule which can be affixed to the esophagus during gastroscopy and a belt meter to determine ph for 48 hrs after which it is excreted) or NG tube acid determination. If Barrett’s esophagus is present the time of gastroscopy, biopsies should be obtained according to current GI standards. Barrett’s esophagus and adenocarcinoma occur at an earlier age in this patient group.
6) Blepharitis is common and can be treated with baby shampoo. High myopia is common and two patients with high myopia developed detached retinas so one should be aware of this association.
7) SIB, anxiety, and aggression may worsen with age, so psychiatric surveillance is important.
8) Figure 1 shows a progression of changes in facial morphology as the patient ages. The changes however, do not occur at all in some patients and occur at different ages from patient to patient. One patient’s facial appearance may change in a different way and at a different age than another patient, so that pictures of patients in childhood demonstrating more “typical” features may be important.  It is prudent to be aware that a middle-aged adult may appear older than his or her stated age and have an elongated face and nose with sagging facial tissue.
9) A DEXA scan should be obtained in all adolescents and young adults with Cornelia de Lange syndrome.
10) The diagnosis is clinical in the proband.

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