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Cytomegalovirus Infection
PEDIATRICS Vol. 113 No. 1 January 2004, pp. 136-141

EXPERIENCE AND REASON—Briefly Recorded

A Novel Developmental and Immunodeficiency Syndrome Associated With Intrauterine Growth Retardation and a Lack of Natural Killer Cells

Frédéric Bernard, MD, PhD*,{ddagger}, Capucine Picard, MD*,§, Valérie Cormier-Daire, MD, PhD||, Céline Eidenschenk, MSc§, Graziella Pinto, MD, Jacinta-Cecilia Bustamante, MD§, Emmanuelle Jouanguy, PhD§, Dominique Teillac-Hamel, MD#, Virginie Colomb, MD, PhD**, Isabelle Funck-Brentano, MSc*, Véronique Pascal, PhD{ddagger}{ddagger}, Eric Vivier, PhD, DVM{ddagger}{ddagger}, Alain Fischer, MD, PhD*,§§, Françoise Le Deist, MD, PhD§§,|||| and Jean-Laurent Casanova, MD, PhD*,§

* Unité d’Immunologie-Hématologie Pédiatrique
|| Service de Génétique
Service d’Endocrinologie Pédiatrique
# Service de Dermatologie
** Service de Gastro Entérologie Pédiatrique
§§ Institut National de la Santé et de la Recherche Médicale (INSERM) U429, Pavillon Kirmisson
|||| Laboratoire d’Immunologie Pédiatrique, Hôpital Necker-Enfants Malades, Paris, France
{ddagger} Hémato-Oncologie Pédiatrie, Pédiatrie 3, Hôpital Arnaud de Villeneuve, Montpellier, France
§ Laboratoire de Génétique Humaine des Maladies Infectieuses, Université René Descartes, INSERM U550, Faculté de Médecine Necker, Paris, France
{ddagger}{ddagger} NK cells and Innate Immunity, Centre d’Immunologie de Marseille-Luminy, Centre National de la Recherche Scientifique-INSERM-Université de la Méditerranée, Campus de Luminy, Case 906, Marseille, France

ABSTRACT

Objective. To describe a novel syndrome characterized by severe prenatal and postnatal growth failure, mild skeletal and facial abnormalities, and primary immunodeficiency.

Design. The syndrome was observed in 2 sisters. The elder child died of cytomegalovirus infection when she was 18 months old, whereas the younger sister is doing well at 5 years old. We report here clinical, hematologic, and immunologic data for both sisters and compare them with all known inherited disorders with similar clinical or immunologic features.

Results. The immune defect consists of a lack of detectable natural killer cells and small numbers of CD8 {alpha}ß T cells and polymorphonuclear neutrophils. This is the first report of prenatal and postnatal growth failure associated with mild skeletal and facial abnormalities and primary immunodeficiency.

Conclusion. This novel syndrome probably is caused by an autosomal recessive gene defect impairing both intrauterine growth and natural killer cell development. The identification of other kindreds with this syndrome would facilitate the search for its genetic basis.

Key Words: intrauterine growth retardation • dysmorphy • primary immunodeficiency • NK cells • viral disease

Abbreviations: PID, primary immunodeficiency disease • NK, natural killer • Ig, immunoglobulin • CMV, cytomegalovirus • SD, standard deviation • OFC, occipitofrontal circumference • GH, growth hormone • IGF1, insulin-like growth factor 1 • WBC, white blood cell • TcR, T-cell receptor • SCID, severe combined immunodeficiency • IL, interleukin

More than 100 primary immunodeficiency diseases (PIDs) have been clinically and immunologically characterized. Most of these PIDs have now been characterized at the molecular genetic level.1,2 PIDs result in qualitative and/or quantitative abnormalities in various cell types (B lymphocytes, T lymphocytes, natural killer [NK] lymphocytes, phagocytes, and dendritic cells) involved in immune responses to infectious agents. The clinical spectrum of PID ranges from a life-threatening lack of leukocytes in neonates with reticular dysgenesis to isolated immunoglobulin (Ig)A deficiency, which is generally asymptomatic even in adults.1,2

Although many PIDs have exclusively immunologic manifestations, other hematopoietic cells may be affected (such as platelets) in patients with Wiskott-Aldrich syndrome.1,2 Immune defects may also be associated with a number of other recognizable extrahematopoietic phenotypic traits.3 The molecular abnormalities associated with these syndromes may affect the development and function of specific organs. For example, bone abnormalities result in generalized growth retardation in patients with some inherited conditions such as cartilage hair hypoplasia and Schimke immuno-osseous dysplasia.1,2

We report the cases of 2 sisters with a complex syndrome including 1) a PID characterized by mild neutropenia, low peripheral CD8+ T {alpha}ß cell counts, and a lack of NK cells and 2) severe prenatal and postnatal growth failure with mildly dysmorphic features and normal intelligence. One child died at 18 months old from cytomegalovirus (CMV) disease. The younger sibling is now well at 5 years old. This combination of PID and intrauterine growth retardation differentiates this syndrome, which is probably novel, from previously reported syndromes.

CLINICAL REPORTS

The proband, patient 1 (II.1), was a girl born in 1993 at 37 weeks of gestation to nonconsanguineous French parents. The pregnancy was uneventful, and the mother did not consume alcohol or suffer from any known infectious diseases. Minor facial abnormalities were noted, including a flat nasal bridge, blepharophimosis, posteriorly rotated ears, and a thin upper lip (Fig 1). The child weighed 1.780 kg at birth (–3 standard deviations [SD] from the mean), was 42 cm long (–4 SD), and had an occipitofrontal circumference (OFC) of 32 cm (–3 SD). The patient still suffered from severe proportionate growth retardation at the 18 months old, with a height of 64 cm (–4 SD), a weight of 6.800 kg (–3.5 SD), and an OFC of 45 cm (–1.5 SD). Intestinal malabsorption was excluded. Endocrinologic tests showed that serum growth hormone (GH) concentrations were increased slightly (by 6.5 ng/mL) after glucagon stimulation and that concentrations of insulin-like growth factor 1 (IGF1) were below normal (0.6 U/mL). Bone age was retarded by an estimated 6 months at a chronological age of 9 months.


Figure 1
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  		Fig 1. Patient 1 at 10 months (A and B) and patient 2 at 24 months (C and D) are shown. Note the minor facial abnormalities including a flat nasal bridge, mild posteriorly rotated ears, thin and horizontal eyebrows, and a thin upper lip in both patients. Shown also is patient 2 at 4 years of age (E and F). Note the wide nasal bridge, flared nostrils, and thick lower lip.

 
At 5 months old, histologic examination of the patient’s skin revealed diffuse acute eczema, consistent with a diagnosis of atopic dermatitis. This was complicated rapidly by generalized erythroderma desquamativum with secondary alopecia and loss of eyebrows. Long-term local steroid treatment and a brief course of parenteral steroids resulted in only a partial clinical response. A new episode of erythroderma was noted when she was 9 months old, with hyper-IgE (29 390 kIU/L). At 1 year old, a first episode of pneumonia occurred, with leukoneutropenia and hypereosinophilia (white blood cell [WBC] count of 4.1 x 109/L, with 697 neutrophils/mm3 and 2460 lymphocytes/mm3). No infectious agent was found in the blood or expectoration, but the patient responded well to antibiotics. At 18 months old, a second episode of pneumonia occurred. This episode was associated with disseminated erythroderma and bullous eruptions suggestive of Lyell’s syndrome. Staphylococcus was not cultured from the skin or blood samples. Urine samples and bronchoalveolar lavage specimens tested positive for CMV. Specific anti-CMV IgG concentrations were high in serum, and no IgM was detected. The patient died after hemodynamic failure (Table 1).


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  		TABLE 1. Clinical and Biological Phenotypes of the 2 Patients

 
At the time of this patient’s final hospitalization, she had low numbers of polymorphonuclear neutrophils and a low CD8+ T-cell count. She had a WBC count of 5.7 x 109/L, with 684 neutrophils/mm3 and 3534 lymphocytes/mm3. There were 34% CD19+ cells, 62% CD2+ cells, 61% CD3+ cells, 49% CD4+ cells, and 9% CD8+ cells. No CD2+ CD3– cells were found, suggesting that there were no NK cells, but a CD16/CD56 study was not performed. Mitogen-stimulation tests were normal (phytohemagglutinin antigen: 85 cpm x 103; CD3: 29 cpm x 103). T-cell responses to antigen stimulation were weak (tetanus toxoid: 2 cpm x 103; candidin: 1 cpm x 103). The T-cell receptor (TcR) Vß2 repertoire profile was normal (Vß2/CD4: 10%; Vß2/CD8: 3%). Ig levels were normal except for IgA, which was present in larger-than-normal amounts (IgG: 8.2 g/L [3.1–18 g/L]; IgA: 1.7 g/L [0.3–1.2 g/L]; IgM: 1.08 g/L [0.5–2.2 g/L]).

The mother had one spontaneous abortion at 8 weeks of amenorrhea in 1997 (II.2). During the following pregnancy in 1998, prenatal ultrasound detected oligohydramnios and intrauterine growth retardation. Chromosome analysis of amniotic cells was normal. A infant girl, patient 2 (II.3) was born at 38.5 weeks’ gestation. She weighed 1.720 kg at birth (–3.5 SD), was 45 cm long (–3.5 SD), and had an OFC of 33 cm (–2 SD). Growth retardation persisted after birth. At 14 months old, she weighed 5.8 kg (–3.5 SD) and measured 66.5 cm (–3.5 SD). The child is now 5 years old; her weight is –3 SD, and her height is –2 SD (height, 90 cm; weight, 10.8 kg) with an OFC of 47 cm (–1.5 SD). Endocrinologic tests showed that serum IGF1 concentrations were normal (89 ng/mL), as was the basal concentration of GH (2 ng/mL). However, GH concentration increased after glucagon stimulation (11 ng/mL). The patient has normal neurologic development including chronological language development and reasoning.

Radiographs of the skeleton showed significant diffuse osteopenia with mild irregular metaphyseal splaying of the long bones and round epiphyses. Bone age was retarded by an estimated 2 years at a chronological age of 3.5 years. Facial abnormalities including blepharophimosis, a flat nasal bridge, prominent round tip of the nose, posteriorly rotated ears, and mild axial hypotonia were noted at birth. At 9 months old, a high forehead, horizontal and thin eyebrows, an epicanthus, small mouth with a thin vermilion border of the upper lip, and cutaneous syndactyly of the second, third, and fourth toes of both feet were noted (Fig 1). The facial dysmorphism was similar to that observed in the patient’s sister. No other developmental, clinical, or radiologic abnormalities were observed.

Eczematous lesions appeared when she was 17 months old. Intolerance to the proteins in cow’s milk was suspected, and modification of the diet led to mild improvement. The child is now doing well on a normal diet and has no detectable cutaneous or digestive illness. The patient has been on continuous prophylactic antibiotic therapy (cotrimoxazole) since 17 months old because of neutropenia and has shown no signs of clinical infection. No antibodies against all viruses tested (herpes simplex virus, CMV, Epstein-Barr virus, and varicella-zoster virus) have been detected in serum. The patient recently began attending a child care center. The relevant clinical parameters for this patient are summarized in Table 1.

Immunologic investigations conducted 4 days after birth revealed leukopenia with neutropenia (3.0 x 109/L WBC with 750 polymorphonuclear neutrophils/mm3). A bone marrow aspirate collected at the same time was normal. Leukoneutropenia persisted until follow-up at 5 years old (Table 2). The CD8+ T {alpha}ß cell fraction was small until she was 3 years old. This was particularly true of the memory CD45RO fraction, whereas the naive CD45RA fraction of CD8 T cells was normal. Very few NK cells (as identified on the basis of CD16–56 expression and a lack of NK activity [K562 killing, even after stimulation by efficient cytokines]) were detected (<1%; Table 2). Patient 2 had an abnormal population of T cells that expressed NK markers (5%; Table 2). High-resolution lymphocyte karyotype was normal, without a high breakage rate after clastogenic stress. Serum Ig concentrations were normal (Table 2). Antibody responses to protein and polysaccharide antigens were also normal. Mitogen- and antigen-driven T-cell stimulation results were normal (Table 2). Levels of {alpha}ß/{gamma}{delta} expression (91%/8%) and TcR Vß repertoire profile (Vß2/CD4: 13%; Vß2/CD8: 8%) were normal. The relevant hematologic and immunologic data are summarized in Table 2.


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  		TABLE 2. Hematologic and Immunologic Parameters of Patient 2 From 4 Days to 3 Years Old

 

DISCUSSION

Both sisters had neutropenia and a low CD8 {alpha}ß T-cell fraction (mostly CD45RO, memory cells). Patient 2 had a characteristic lack of NK cells. Patient 1 probably also lacked NK cells, although the NK cell count could only be estimated indirectly from the number of CD2+CD3– cells. Interestingly, the deficiency of memory CD8 cells was transient, and the numbers of these cells were nearly normal in patient 2 by 3 years old (patient 1 died at 18 months). Both siblings constantly had mild neutropenia, low CD8 counts, and a lack of NK cells. No other immunologic abnormalities were noted. These features are not consistent with any known PID.1,2 In particular, the most common forms of NK deficiency are associated with several forms of severe combined immunodeficiency (SCID). NK lymphocytes cannot be detected in subjects with X-linked T–B+NK– SCID (in which the gene encoding the common {gamma} receptor chain of the interleukin [IL]-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptors is mutated)6 or autosomal recessive T–B+NK– SCID (in which the gene encoding JAK-3 is mutated).7 An NK-deficient form of combined immunodeficiency with a low T-cell count was described recently.8 Levels of the IL-2R/IL-15Rß chain were significantly reduced in the patient’s peripheral blood mononuclear cells, but no mutations were found in the coding sequence of the IL2R/IL15Rß chain gene. However, in these conditions, the lack of NK cells was associated with severe T-cell lymphopenia and/or impaired T-cell responsiveness, which was not the case in the patients described here.

There has been only one report of a patient with a specific and complete lack of detectable NK cells.9 The patient had a marked susceptibility to herpes viruses. She presented a life-threatening varicella virus infection at 13 years old and subsequently developed severe CMV and herpes simplex virus infections. There was no detectable developmental phenotype, and her immune functions, except for the deficiency of NK cells, were otherwise normal. It is not known whether the NK defect preceded the viral infections, and no clinical follow-up since 1989 has been reported. The elder of the 2 sisters described here (patient 1) died of CMV infection. Despite having extremely low NK cell counts, patient 2 has suffered no obvious severe infections, although she has never been exposed to any known herpes viruses. The mouse model of CMV infection recently provided genetic evidence that NK cells contribute to antiviral immunity.10,11 Together with the previous case of NK deficiency,9 our observations suggest that human NK cells play a role in immunity to CMV after natural infection,12 although the CD8 T-cell deficiency may also have played a significant role.

Prenatal growth retardation has only been described in a few PIDs (Table 3). Intrauterine growth retardation is a classical component of immunodeficiency syndromes involving chromosomal instability and defective DNA repair. Bloom’s syndrome13 is characterized by sensitivity to light, high susceptibility to malignancies, weak T-cell function, and low serum IgM concentrations. Fanconi’s aplastic anemia is characterized by multiple organ defects including bone marrow failure. Decreases in T-lymphocyte counts and serum IgA concentrations have been described.14 "Bird-like" facies syndromes such as Seckel syndrome15 and Nijmegen breakage syndrome16 are characterized by dwarfism (intrauterine onset) and mental retardation. Some affected individuals have low serum Ig concentrations, but NK cell counts are normal. Prenatal growth retardation has also been observed in patients with Schimke immuno-osseous dysplasia, which is characterized by skeletal dysplasia, nephropathy, pigmentary skin changes, and T-cell function defects.17


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  		TABLE 3. Differential Diagnosis

 
Some PIDs are characterized by normal intrauterine development, but postnatal growth retardation is associated with bone lesions (Table 3). Most of these PIDs are associated with a normal NK cell count. The only exception is adenosine deaminase deficiency, which causes an autosomal recessive form of SCID characterized by pronounced T, B, and NK cell lymphopenia.18 Cartilage-hair hypoplasia is a recessively inherited developmental disorder with metaphyseal dysplasia caused by mutations in the RNA component of ribonuclease mitochondrial RNA-processing endoribonuclease. It is associated with variable lymphopenia, low CD4+ cell count, low total T-lymphocyte count and a normal NK cell count.19 The molecular bases of short-limbed skeletal dysplasia,20 in which stature is reduced disproportionately, and combined immunodeficiency, which leads to short-limbed dwarfism and ectodermal dysplasia,21 remain to be elucidated. A small number of B cell immunodeficiencies associated with growth retardation and bone abnormalities have been described, including antibody-mediated immunodeficiency with short-limbed dwarfism22 and Roifman syndrome.23 However, these have yet to be characterized at the molecular level. All these syndromes were easily excluded on clinical, radiologic, and biological grounds in our 2 patients.

The clinical characteristics of the 2 children described here also differ from those of patients with severe short-stature syndromes with intrauterine growth retardation and normal mental development (in which PID is not a known characteristic of the syndrome). We excluded the possibility of chromosomal defects, because the patient’s karyotype was normal. The syndrome is also different from other primary forms of dwarfism (Table 3). Our patients have never had any GH abnormalities or any other features suggestive of pituitary dwarfism or pseudopituitary dwarfism; for example, GH and IGF1 concentrations and blood glucose concentration were normal. Indeed, GH deficiency or GH insensitivity with mutations in the GH receptor gene (Laron syndrome)24 or in the IGF1 gene25 were excluded. Other syndromes such as Dubowitz syndrome were rapidly excluded because these syndromes are associated with different malformations, microcephaly, and mental retardation.26 An autosomal recessive syndrome, characterized by severe dwarfism at birth (remaining <5th percentile) and a distinctive gloomy face with full lips, short nose, a large and hypotonic abdomen, long, gracile bones, and good mental development, has been described and has the same features as 3-M syndrome.27 These clinical findings differ from those for the 2 siblings reported here. Silver-Russell syndrome can also been excluded. In addition to prenatal and postnatal short stature, this syndrome is characterized by relative macrocephaly, distinct facial dysmorphy (triangular facies), 5th-finger clinodactyly, and limb asymmetry.28 We also excluded a diagnosis of floating-harbor syndrome, characterized by short stature with bone growth retardation and a characteristic facial appearance, which is usually recognized in children with mild retardation in the acquisition of expressive language.29 The syndrome described here therefore clearly differs from all known PIDs and from all intrauterine growth retardation syndromes.

We describe here 2 sisters with severe prenatal and postnatal growth defects associated with mild skeletal and facial abnormalities and a PID. This PID is principally marked by a lack of detectable NK cells, mild neutropenia, and a low CD8+ T-cell count. This combination of developmental and immunologic abnormalities has not been reported before. The fact that the same syndrome occurred in 2 sisters suggests an autosomal recessive mode of inheritance, although other types of inheritance such as autosomal dominance with germ-line mosaicism cannot be strictly excluded. Identification of the underlying genetic defect will provide insight into the mechanisms governing NK development and intrauterine growth. The identification of other kindreds with this syndrome would greatly facilitate the search for its genetic basis.

ACKNOWLEDGMENTS

C. Picard was supported by an Institut National de la Santé et de la Recherché Médicale grant. This work was supported by Fondation BNP-Paribas and Fondation Schlumberger.

We thank members of Institut National de la Santé et de la Recherché Médicale U550 for helpful discussions.

FOOTNOTES

Received for publication Jan 6, 2003; Accepted May 15, 2003.

Address correspondence to Jean-Laurent Casanova, MD, PhD, Laboratoire de Génétique Humaine des Maladies Infectieuses, Université René Descartes, INSERM U550, Faculté de Médecine Necker, 156 Rue de Vaugirard, 75015 Paris, France. E-mail: casanova{at}necker.fr

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PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics



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