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Shprintzen syndrome

22q11.2 deletion syndrome (also called DiGeorge syndrome and velocardiofacial syndrome) is a disorder caused by the deletion of a small piece of chromosome 22. The deletion occurs near the middle of the chromosome at a location designated q11.2. more...

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The features of this syndrome vary widely, even among members of the same family, and affect many parts of the body. Characteristic signs and symptoms include heart defects that are often present from birth, an opening in the roof of the mouth (a cleft palate or other defect in the palate), learning disabilities, recurrent infections caused by problems with the immune system, and mild differences in facial features. Affected individuals may also have kidney abnormalities, low levels of calcium in the blood (which can result in seizures), significant feeding difficulties, autoimmune disorders such as rheumatoid arthritis, and an increased risk of developing mental illnesses such as schizophrenia and bipolar disorder.

Because the signs and symptoms of 22q11.2 deletion syndrome are so varied, different groupings of features were once described as separate conditions. Doctors named these conditions DiGeorge syndrome, velocardiofacial syndrome (also called Shprintzen syndrome), and conotruncal anomaly face syndrome. In addition, some children with the 22q11.2 deletion were diagnosed with Opitz G/BBB syndrome and Cayler cardiofacial syndrome. Once the genetic basis for these disorders was identified, doctors determined that they were all part of a single syndrome with many possible signs and symptoms. To avoid confusion, this condition is usually called 22q11.2 deletion syndrome, a description based on its underlying genetic cause.


Individuals with a 22q11 deletion have a range of findings, including:

  • Congenital heart disease (74% of individuals), particularly conotruncal malformations (tetralogy of Fallot, interrupted aortic arch, ventricular septal defect, and truncus arteriosus)
  • palatal abnormalities (69%), particularly velopharyngeal incompetence (VPI), submucosal cleft palate, and cleft palate; characteristic facial features (present in the majority of Caucasian individuals)
  • learning difficulties (70-90%)
  • an immune deficiency regardless of their clinical presentation (77%)
  • hypocalcemia (50%)
  • significant feeding problems (30%)
  • renal anomalies (37%)
  • hearing loss (both conductive and sensorineural)
  • laryngotracheoesophageal anomalies
  • growth hormone deficiency
  • autoimmune disorders
  • seizures (without hypocalcemia)
  • skeletal abnormalities

Thymus, parathyroid glands and heart derive from the same primitive embryonic structure and that is why these three organs are dysfunctioned together in this disease. Affected patients (usually children) are prone to yeast infections.


The disease is related with genetic deletions (loss of a small part of the genetic material) found on the long arm of the 22nd chromosome. Some patients with similar clinical features may have deletions on the short arm of chromosome 10.


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Evidence that the association between hypernasality and 22q11 deletion syndrome still goes undetected: A case study
From American Journal of Speech-Language Pathology, 8/1/00 by Greenberg, Irit Spierer

This manuscript presents a case study that underscores the need for increasing awareness that hypernasality, velopharyngeal insufficiency, and a number of other anomalies may be related through the common etiology of 22q11 deletion syndrome. The child presented here has a long-standing history of cardiac defects, hypernasality, poor speech intelligibility, and other anomalies. The variety of symptoms, occurring over a relatively broad time span, caused the family to seek several individual specialists on separate occasions. A major factor influencing this case was the

absence of communication between the various specialists. Each health care specialist treated the child based on the limited perspective of the individual discipline, missing the fundamental etiology of the child's disorders. It was not until the diagnosis of 22q11 deletion syndrome was established that successful, coordinated treatment of the disorder was realized.

Key Words: 22q11 deletion syndrome, hypernasality, cardiac anomalies, velo-cardio-- facial syndrome, interdisciplinary assessment, craniofacial

What we now know as 22q 11 deletion syndrome was originally considered as separate elements of DiGeorge syndrome (DGS), velo-cardio-- facial syndrome (VCFS), and conotruncal anomaly Lace syndrome (CTAF). Although these syndromes have been described separately, many of the features found in each overlap. DGS syndrome is a pattern of malformation that is characterized by absent or hypoplastic thymus and parathyroid glands, conotruncal cardiac malformations, and facial anomalies (i.e., short palpebral fissures, micrognathia, etc.) (Jones, 1997; Carneol, Marks, & Weik, 1999). VCFS is a congenital malformation syndrome involving cleft palate, congenital cardiac anomalies, characteristic facial appearance, and learning disabilities (Shprintzen et al., 1978; Shprintzen, Goldberg, Young, & Wolford, 1981). CTAF syndrome is characterized by conotruncal cardiac anomalies, atypical facial features, and developmental delay (Wulfsberg, Cox, & Giovanni, 1996). Despite initial reports that these were distinct entities, it is now recognized that the coexistence of the symptoms associated with these disorders results from the same deletions in chromosome 22q1 (Leana-Cox, Pangkanon, Eanet, Curtin, & Wulfsberg, 1996).

The facial features associated with 22Q11 deletion syndrome may include a long face with a flat malar region, long prominent nose with or without a broad nasal bridge and bulbous tip, narrow palpebral fissures, slanted eyes, small mouth, micrognathia, retrognathia, external ear anomalies, and abundant scalp hair (Carneol et al., 1999). In addition, cleft palate or velopharyngeal insufficiency resulting in hypernasal speech, and general developmental delays have also been associated with this deletion (Leana-- Cox et al., 1996). Shprintzen (1997) stated, "Speechlanguage pathologists and audiologists are very likely to encounter velo-cardio-facial syndrome in their clinical practices because nearly all children with this disorder have hypernasality and severe articulatory impairment." Thus, it should be clear that although hypernasality or any of these other symptoms can signal different etiologies, chromosome 22q 11 deletions should be considered when a patient presents with one or more of the above anomalies.

Early investigations reported an estimate of at least 1:20,000 cases of DGS and VCFS, with a combined incidence of 1: 10,000. More recent estimates of occurrence of 22ql I deletions are 1:5,000 and are thought to account for 5% of all newborns with heart defects (Thomas & Graham, 1997). Affected individuals have a 50% risk of transmitting the 22ql 11 deletion to their offspring (Driscoll et al., 1993). A recent European collaborative study (Ryan et al., 1997) presented clinical data on 558 patients with deletions within the region of chromosome 22q 11. In their data, Ryan et al. showed that 32% of the patients had velopharyngeal insufficiency, 75% had cardiac problems, 9% had cleft palate, and the majority were of small stature, with 36% falling below the 31 percentile for parameters of height or weight. In another study, Young, Shprintzen, and Goldberg (1980) showed that 85% of their sample with 22ql 11 deletions had congenital cardiovascular malformations, which included ventriculoseptal defect, tetralogy of Fallot, and interrupted aortic arch. It was reported that individuals with VCF have abnormalities in several major arteries, including the internal carotid artery, the vertebral artery, and those arteries found in the pharynx (Sphrintzen, 1997). Thus, if surgery is prescribed as a treatment for hypernasality without prior knowledge of VCF, serious surgical complications may be encountered (Sphrintzen, 1997). The compilation of possible symptoms and related medical disorders is shown in Table I (Carneol et al., 1999; Ryan et al., 1997; Shprintzen et al., 1981; Thomas & Graham, 1997; Williams, Shprintzen, & Goldberg, 1985).

Here, we present a case study that illustrates how chromosome 22ql 11 deletion in a patient with several classic symptoms went undetected for several years even though numerous health care providers evaluated her. Our purpose is to emphasize identification of this particular genetic defect for the proper diagnosis of patients with the constellation of symptoms described above.

Case Study

Presenting Concerns

A 5-year-old female born with tetralogy of Fallot (TOF) was brought by her mother for a speech and language evaluation due to concerns of persistent hypernasality from the age of 2 years. TOF is a congenital cardiac malformation consisting of pulmonary stenosis, ventricular septal defect, overriding aorta that receives blood from both ventricles, and hypertrophy of the right ventricle (Wong, 1995). The child had been receiving speech and language treatment for 3 years with slow progress as reported by her mother. A speech and language evaluation completed approximately 2 years before the current evaluation revealed a severe receptive and moderate expressive language delay and a severe articulation disorder with inadequate production of plosive sounds (/k/, /g/, /p/, /b/, /d/, /t/) and fricative sounds (/s/, /z/, etc.). Hypernasal speech with poor intelligibility was also noted. Hearing sensitivity was found to be normal based on air conduction screening completed through the public school system.

At the time of the present evaluation, the child was receiving speech treatment 5 days per week. Early treatment focused on improving overall language abilities. Subsequent treatment goals, as noted in the individual education plan (IEP), were aimed at increasing intelligibility of speech by targeting high-pressure phonemes (fricatives and plosives).

Medical History

The patient was born full term and underwent a balloon valvuloplasty at 3 months of age to alleviate cyanosis. She subsequently had open-heart surgery and 2 cardiac catheterizations with complete repair of her TOF at approximately 1 1/2 years of age. At 2 years of age she was seen at a hospital clinic for a follow-up cardiology evaluation for status post-TOF and mild acquired pulmonary regurgitation. At age 4 years, she was evaluated at an otolaryngology clinic with the presenting concern of significant speech delays. She had 4+ tonsilar and adenoidal hypertrophy, bilateral otitis media, and flat tympanograms. The patient was treated with antibiotics and returned for a follow-up visit to an otolaryngologist one month later. Upon resolution of these symptoms, it was recommended that she continue with speech treatment with follow-up in one year. The patient was also seen at a cardiology clinic at 4 years of age. She was found to be doing well from the cardiovascular standpoint and was "growing and developing normally except for a speech delay." At approximately 5 years of age she was seen by a radiologist for a magnetic resonance computerized tomography (MR CT) scan of the nasopharynx. Radiological findings indicated a "prominence of lymphoid tissue in the oropharynx and nasopharynx with no evidence of airway encroachment."

Developmental History

The mother reported that the child had lactose intolerance as an infant and was given soy. She snored during sleep. Gross motor developmental milestones were achieved within age-level expectations. She was delayed in the acquisition of single-word utterances, which was reported to begin at 18 months of age, and she did not produce two-word utterances until the age of 31/2 years. Several multidisciplinary teams in the public school system evaluated this child to determine her developmental status. Cognitive testing, completed when she was 3 years 2 months old, indicated overall functioning was in the low range and nonverbal abilities were particularly low. Standard scores of 72 (General Conceptual Abilities) and 68 (Nonverbal Cluster) were based on results of the Differential Abilities Scale (DAS; Elliott, 1990). In kindergarten she was placed in a special education class for educable children with mental retardation.

Speech and Language Findings

The first author saw the child at the age of 5 years 1 month. Physical findings consisted of a very small head, a flat occipital area, and short stature for her age. Head circumference and height measurements were more than 2.0 standard deviations below the mean for her age. She exhibited mild dysmorphic features that consisted of a prominent forehead and a slightly broad nose. Standardized measures of language development indicated severe generalized language delays in all domains of language acquisition (see Table 2).

Measures of receptive and expressive vocabulary development revealed severe delays. Acquisition and use of morphological markers and syntactic development were also severely delayed. Pragmatic deficits were evident in her difficulty maintaining the topic of conversation, verbal perseveration, and limited use of questions. Examination of the oral peripheral mechanism revealed a hyperactive gag reflex and hypertrophied tonsils. Oral functional evaluation revealed difficulty moving the tongue independent of the jaw during lateralization, suggesting oral motor immaturity. In addition to persistent hypernasality, she exhibited a severe phonological disorder as measured by the Assessment of Phonological Processes-Revised (APP-R; Hodson, 1986). Speech intelligibility ranged from poor to fair depending on whether contextual cues were available to the listener. Particular difficulty was noted in production of velar phonemes, stridents, and liquids (/l/, /r/).

As a result of these clinical findings and because we did not have appropriate equipment at this facility, the child was referred to a neighboring site for a resonance evaluation and assessment of the velopharyngeal mechanism by consultation. Test results, using flexible fiberoptic video-- nasoendoscopy (FFVN) to image the vocal tract and a Kay Elemetrics Nasometer to obtain objective nasalance measures, showed velopharyngeal insufficiency and severe nasal resonance. Perceptual assessment of conversational speech using the Wilson Profile (Wilson, 1990) yielded an overall severity rating of 5 (moderate) on a 7-point scale. Because of the surgical risk factors associated with VCF, magnetic resonance angiography was recommended to the family to determine whether surgery was an option for treatment of velopharyngeal insufficiency (Mitnick, Golding-Kushner, Argaaso, & Shprintzen, 1996; Shprintzen, 1997). A palatal lift prosthesis was considered as an alternative to improve nasal resonance in the event that surgery was ruled out. In conjunction with these additional evaluation procedures, a treatment intervention plan was developed that focused on improving articulatory precision and intelligibility of speech.

The child was also referred for a genetic evaluation, given her early history of cardiac problems, longstanding history of hypernasality, speech and language difficulties, cognitive delays, and microcephaly, to determine whether the multiple anomalies were genetically linked. As a result of the physical examination, detailed chromosomal studies were ordered. FISH probe revealed a deletion at 22qI 11.2. For this child's mother, cytogenetic studies and prenatal testing were recommended in the event of future pregnancies, because individuals with this deletion have a 50% risk of transmitting the deletion to their offspring (Ryan et al., 1997).


Carneol et al. (1999) reported a case similar to this child. However, in that report the suspicion of 22Q1 I deletion syndrome was raised because there was significant family history, which included other siblings' symptoms (i.e., TOF, hypernasality, articulation delays, physical features), as well as the mother's phenotype (i.e., hypernasality secondary to an occult submucous cleft palate). In contrast, the child in our study had no familial link highlighting the possibility of nouveau incidences of such genetic disorders.

The wide spectrum of symptoms that occur with 22q II deletions range from cardiac anomalies to hypernasality and language or learning disorders. Such a wide variety of problems require the expertise of numerous specialists. Thus, it is reasonable to expect, for example, that a health care provider treating a cardiac problem may not be aware that coexisting hypernasality and/or other speech difficulties are from the same genetic cause. Likewise, an otolaryngologist treating hypernasality, velopharyngeal insufficiency, and other symptoms may not be cognizant of underlying cardiac-related problems. The child in this case study underwent balloon valvuloplasty at 3 months of age followed by other cardiac procedures in subsequent years. It is unlikely that hypernasality or other speech abnormalities were detectable at that early age. Because of the time span between the early cardiac surgery and the age at which the other speech and language problems were detected, significant challenges exist in correlating the clinical symptoms to the 22q 11 deletion syndrome. As the child in this case study grew older and the other symptoms became apparent (i.e., hypernasality, learning difficulties, speech and language difficulties, and microcephaly), no connection was made between her cardiac problems, these other symptoms, and 22q1 I deletion syndrome. It is plausible to assume the likelihood of early identification of 22q 11 deletion syndrome would be based on the early cardiac symptoms combined with speech and language abnormalities. In the case of this child, early identification of 22q 11 deletion syndrome would have allowed for early intervention to occur in multiple domains of articulation difficulties, hypernasality, language delays, and delays in cognitive development. Because early identification of 22qI 11 deletion syndrome was not made, this child was treated for individual symptoms without knowledge of the underlying cause. This led to limited planning for intervention and resulted in unsuccessful treatment outcomes as symptoms such as difficulty producing high-pressure phonemes (fricatives and plosives) paired with hypernasality continued to manifest themselves over the first 5 years of her life. Lack of intervention success was also manifested as frustration on the part of the parents in addition to increased expense for the intervention of each individual symptom. Once appropriate diagnosis of 22q 11 deletion syndrome was established for this child, a coordinated plan of care and intervention was developed that took into consideration her cardiac status, otolaryngological follow-up care, speech and language intervention, and educational placement and intervention.

There are suggestions that 22ql 11 may be more common than previously thought (Ryan et al., 1997). When the symptoms of this syndrome are viewed narrowly through the perspective of one discipline, the syndrome itself can be missed. This is significant because the global effects can be far-reaching with respect to medical, surgical, speech, language, and educational interventions. The role of genetics in identifying this syndrome is particularly important. This is true not only for a timely diagnosis but also for family counseling and planning for future pregnancies. The review of this child's case also emphasizes the need to obtain history information beyond the normal scope of questioning rendered by most speech-language pathologists. Particular focus on the cardiac history in addition to close observation of cranio-facial features and speech/language delays offer the potential for appropriate consultations leading to early diagnosis and intervention for the total range of symptoms associated with 22ql 11 deletion syndrome.

Author Note

Further information may be obtained from the VCFS Education Foundation at: Communication Disorder Unit, University Hospital, 750 Adams St., 708 Jacobsen Hall, Syracuse, NY 13210; phone number: 315-464-6590; Web site:


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Received September 13, 1999 Accepted June 30, 2000

Irit Spierer Greenberg

Robert C. Fifer

University of Miami, Mailman Center for Child Development, Miami, FL

Contact author: hit S. Greenberg, MS, University of Miami, Mailman Center for Child Development, P.O. Box 016820, Miami, FL 33101

Copyright American Speech-Language-Hearing Association Aug 2000
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